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The Nuclear Lamina

Xianrong Wong,1 Ashley J. Melendez-Perez,2 and Karen L. Reddy2,3

1
Laboratory of Developmental and Regenerative Biology, Skin Research Institute of Singapore,
Agency for Science, Technology and Research (A∗STAR), Singapore 138648
2
Department of Biological Chemistry and Center for Epigenetics, Johns Hopkins University of Medicine,
Baltimore, Maryland 21205, USA
3
Sidney Kimmel Cancer Institute, Johns Hopkins University School of Medicine, Baltimore,
Maryland 21231, USA
Correspondence: kreddy4@jhmi.edu

Lamins interact with a host of nuclear membrane proteins, transcription factors, chromatin
regulators, signaling molecules, splicing factors, and even chromatin itself to form a nuclear
subcompartment, the nuclear lamina, that is involved in a variety of cellular processes such as
the governance of nuclear integrity, nuclear positioning, mitosis, DNA repair, DNA replica-
tion, splicing, signaling, mechanotransduction and -sensation, transcriptional regulation, and
genome organization. Lamins are the primary scaffold for this nuclear subcompartment, but
interactions with lamin-associated peptides in the inner nuclear membrane are self-reinforc-
ing and mutually required. Lamins also interact, directly and indirectly, with peripheral
heterochromatin domains called lamina-associated domains (LADs) and help to regulate
dynamic 3D genome organization and expression of developmentally regulated genes.

T he nucleus is structurally organized into func-

tional domains and, as an interpreter and reg-
ulator of cellular function, is unique between cell
types. In addition to expressing cell-type-specific
transcription factors and genome regulators, this
diversity is also quite evident at the periphery of
the nucleus. The nuclear periphery encompasses
the nuclear envelope and the underlying nuclear
lamina (Aebi et al. 1986). The nuclear envelope is
a dual membrane barrier composed of the inner
nuclear membrane (INM) and the outer nuclear
membrane (ONM), which is contiguous with
the endoplasmic reticulum (ER). The nuclear
envelope (NE) is studded with nuclear pore com-
plexes (NPCs) that span the ONM and INM.
Underlying the INM is the nuclear lamina, a
10- to 30-nm-thick filamentous meshwork,
with its thickness varying between different cell
types (Höger et al. 1991). The principal compo-
nents of the lamina are the type V intermediate
filament proteins—the lamins (Fig. 1; Gerace and
Huber 2012). In mammals, the lamins are
grouped into two classes: A-type (LMNA,
LMNAΔ10, and LMNC) and B-type (LMNB1,
LMNB2, and LMNB3) (Peter et al. 1989; Vor-
burger et al. 1989). All metazoans express at least
one B-type lamin, with most invertebrates ex-
pressing a single lamin gene, although Drosophila
has one B-type (Dm0 or Dmel/Lam) and one
A-type (DmeI/LamC). In mammals, most adult

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X. Wong et al.

Nuclear
integrity

Spindle
assembly

Transcriptional
regulation
Nucleocytoskeletal Nuclear
coupling positioning
Lamins
Splicing

Chromatin
organization

Signaling

DNA
replication DNA repair

Figure 1. Lamins—a critical nexus in the regulation of cellular processes. Lamins and their associated proteins
(lamin-associated proteins [LAPs] and nuclear envelope transmembrane proteins [NETs]) have been implicated
in a wide range of interdependent cellular processes placing lamins at the center of an integrative hub at the
nuclear lamina. Black arrows indicate lamin influences on specific pathways and processes and the gray lines
indicate cross talk between these processes. These processes include maintaining structural integrity of the
nucleus (Shin et al. 2013; Swift et al. 2013; Harada et al. 2014), regulation of transcription through direct
interactions with transcription factors as well as signaling pathways (Andrés and González 2009; Ho and
Lammerding 2012), and three-dimensional chromatin organization (scaffolding of lamina-associated domains
[LADs]) (van Steensel and Belmont 2017; Briand and Collas 2020), which in turn impacts nuclear integrity and
structure, since chromatin and lamins collaborate to confer mechanical properties to the nucleus (Chalut et al.
2012; Furusawa et al. 2015; Shimamoto et al. 2017; Stephens et al. 2017; Strickfaden et al. 2020). The nuclear
lamina and interacting proteins also regulate other DNA-based processes such as DNA replication (Dorner et al.
2006; Shumaker et al. 2008; Pope et al. 2014) and DNA repair (Redwood et al. 2011; Aymard et al. 2014; Gibbs-
Seymour et al. 2015; Lottersberger et al. 2015; Li et al. 2018; Marnef et al. 2019). Linker of nucleoskeleton and
cytoskeleton complex (LINC) proteins mediate nucleocytoskeletal coupling, which in turn influences other
processes such as signaling, chromatin organization, DNA repair, and gene regulation (through mechanosensa-
tion and mechanotransduction) as well as nuclear position through direct interaction of LINCs with cytoskeletal
motors (Razafsky et al. 2014; Wong et al. 2021a). Other identified but less commonly known roles of the lamins
include splicing and spindle pole assembly (Georgatos et al. 1997; Maison et al. 1997; Kumaran et al. 2002; Tsai
et al. 2006; Ma et al. 2009).

differentiated somatic cells contain four major
lamin proteins (LMNA, LMNB1, LMNB2, and
LMNC). A single gene, LMNA, encodes the A-
type lamins LMNA and LMNC, along with other
minor variants including LMNAΔ10, which are
all generated by alternative splicing of a common
pre-mRNA (Lin and Worman 1993; Machiels
et al. 1996; DeBoy et al. 2017). A minor spliced
variant, LMNC2, is also produced in the testis
(Furukawa et al. 1994). Separate genes encode
LMNB1 and LMNB2 with LMNB3 being pro-
duced as a minor spliced variant of LMNB2

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and, as with LMNC2, is found in the testis (Fu-
rukawa and Hotta 1993; Lin and Worman 1993).
All lamin isotypes share a similar overall struc-
ture: a head domain, a central α-helical rod do-
main comprising four coiled-coil domains that
enable lamin dimer formation, interspersed by
unstructured linkers, followed by a nuclear local-
ization signal (NLS), an Ig-fold domain ending in
an unstructured carboxy-terminal tail (detailed
in Fig. 2). The basic unit of the lamins is the lamin
dimer, which forms protofilaments in a head-to-
tail manner and form higher-order assemblies to
make the final lamin filament structure (Dechat
et al. 2010). In mammals, recent high-resolution
light and electron microscopy studies have re-
vealed that the A-, B-, and C-lamin isotypes
form their own spatially separate but interacting
and overlapping filament networks of 3.5-A tet-
rameric filaments (Shimi et al. 2008; Turgay et al.
2017), with lamin C showing an apparent pref-
erential association with nuclear pores (Xie et al.
2016). This makes lamin organization in mam-
malian somatic cells more complex and less reg-
ular than previously observed in the frog oocyte
lamina (Aebi et al. 1986).
REGULATION OF LAMINS
Lamin functions are regulated by a myriad of
posttranslational modifications (PTMs) (see
Fig. 1), especially higher-order assembly into fil-
aments and disassembly during nuclear enve-
lope breakdown as cells enter mitosis. Most
prominently, lamins are regulated by phosphor-
ylation, but are also subjected to farnesylation,
ubiquitination, sumoylation, O-linked sugar
modification (O-GlcNAc), and acetylation (Ge-
race and Blobel 1980; Simon and Wilson 2013;
Kochin et al. 2014; Gruenbaum and Foisner
2015; Torvaldson et al. 2015). While the roles
of the vast majority of phosphorylation and
other modifications to lamin proteins are not
understood, there is a clear role for phosphory-
lation in lamin disassembly in mitosis. Cyclin-
dependent kinase 1 (Cdk1 or cdc2) directly
phosphorylates both A- and B-type lamins dur-
ing mitosis. Phosphorylation of amino-terminal
Serine 22 (S22P) and carboxy-terminal Serine
392 (S392P) in human lamin A/C or analogous
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Nuclear Lamina
residues in B-type lamins near the coiled-coil
domains induce the disassembly of the nuclear
lamina. Intriguingly, a subset of A-type lamins
remains phosphorylated, soluble, and nucleo-
plasmic during interphase (Gerace and Blobel
1980; Kochin et al. 2014; Torvaldson et al.
2015; Ikegami et al. 2020). While S22P is neces-
sary for lamin depolymerization, it is not suffi-
cient; thus, CDK1 is likely working in concert
with other kinases, such as protein kinase C
(PKC), cyclin-dependent kinase 5 (CDK5), and
AKT to facilitate complete disassembly and to
further regulate lamin functions (Torvaldson
et al. 2015). It is important to note that the ma-
jority of PTM sites of lamins have been identified
by mass spectrometry without accompanying
mechanistic and functional studies, so there is
still much to be understood about the dynamic
regulation of lamins through these different
modifications and modification sites.
In addition to being regulated by PTMs (and
splicing), expression of lamin isotypes is also de-
velopmentally regulated, with expression of A-
type lamins (LMNA and LMNC) being restrict-
ed to more differentiated cells, and each cell type
displaying different relative ratios of the different
lamin isotypes. All nucleated mammalian cells
express at least one B-type lamin, whereas A-
type lamins are absent during the early pre-
and postimplantation embryonic stages and in
embryonic stem (ES) cells, with these types ex-
pressing high levels of LMNB1 and LMNB2
(Stewart and Burke 1987; Wong and Stewart
2020). A-type lamins are expressed as different
tissues form in the postimplantation embryo,
although some tissues and cell types do not ex-
press A-type lamins until after birth (Solovei
et al. 2013). Lamins appear to be nonessential
for ES cells, since ES cells and their derivative
progenitors lacking LMNA, LMNC, and
LMNB1 proliferate normally in culture, main-
tain euploidy, and differentiate normally into
multiple cell types (Kim et al. 2013). However,
it should be noted that the ES culture system
reflects early pre-organ development. The story
is not as clear-cut in vivo, although A-type lam-
ins are dispensable for early development. Mice
lacking either LMNA, LMNC, or both are indis-
tinguishable from normal siblings at birth, pos-
3
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X. Wong et al.

A Ubiquitination

Phosphorylation

Acetylation
Sparse: O-GlcNAc,
SUMOylation
Coil 1A Coil 1B Coil 2A Coil 2B Ig fold
CAAX
Head L1 L12 L2 NLS

α-Helical central rod

B
Lamin C

Prelamin A
Farnesyltransferase
AAX endopeptidase
Carboxyl methyltransferase S
COCH3

Zmpste24
Mature lamin A

S
COCH3 Lamin B1 and B2

C Lamin monomer
Mitotic CDKs

Antiparallel arrangement, higher-order assembly

Lamin coiled-coil dimer—basic unit of assembly

Interphase
Phosphatases

Head-to-tail polymerization
into a protofilament
Mitotic exit

Figure 2. Assembly, processing, and regulation of lamins. (A) The general structure of a lamin protein, consisting
of a short unstructured head domain (yellow), a central α-helical rod domain comprised of four helical subre-
gions (coils 1A, 1B, 2A, and 2B in purple) interspersed by unstructured linkers (L1, L12, and L2), a tail region that
includes a nuclear localization signal (NLS) (green), an immunoglobulin-fold domain (Ig-fold) (red), and a fairly
unstructured carboxy-terminal end that in most cases terminates with a carboxy-terminal CAAX motif (Stuur-
man et al. 1998; Krimm et al. 2002; Herrmann and Aebi 2004). (Legend continues on following page.)

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Nuclear Lamina

sibly because of some functional redundancy
with the developmentally regulated INM pro-
tein lamin B receptor (LBR) that is expressed
(or over- or re-expressed) in cells engineered to
lack Lmna (Sullivan et al. 1999; Jahn et al. 2012;
Solovei et al. 2013). Loss of Lmna does, however,
result in severe postnatal growth retardation and
death within 3 weeks, which is correlated to
some extent with the normal silencing of LBR
expression in many postnatal tissues (Sullivan
et al. 1999; Jahn et al. 2012; Solovei et al. 2013).
Intriguingly, the ratio of LMNA/LMNC varies
across different cell types suggesting cell-type-
specific and developmental regulation of LMNA
splicing or posttranscriptional regulation. One
striking example of differential A/C expression
is in neurons where LMNA (and not the LMNC
splice variant) translation is inhibited by the mi-
croRNA miR-9, which binds specifically to the
longer LMNA mRNA 30 UTR (untranslated re-
gion) (Jung et al. 2012). Less is known about the
cell and tissue variation of expression of somatic
B-type lamins. Both LMNB1 and LMNB2 are
required for normal neuronal development
(Vergnes et al. 2004; Coffinier et al. 2011). In
addition, both human and murine fibroblasts
with reduced levels of LMNB1 undergo senes-
cence and display reduced proliferation and loss
of LMNB1 correlates with keratinocyte senes-
cence in vivo (Shimi et al. 2011; Dreesen et al.
2013; Shah et al. 2013). In adults, B-type lamin
expression appears to be nonessential in some
tissues, such as the skin epidermis and liver
(Yang et al. 2011). These findings reveal that
an absolute dependence on lamin expression
in mammals varies among different cell types
and that early embryos, including pluripotent
cells and some of their differentiated derivatives,
may not require any of the lamins for their pro-
liferation and early differentiation.

Figure 2. (Continued) While the rod domain is involved in the dimerization of lamins through coiled-coil
interactions, the head and tail domains play a significant role in regulating the higher assembly of lamins (Gieffers
and Krohne 1991; Heitlinger et al. 1992; Stuurman et al. 1996; Klapper et al. 1997; Sasse et al. 1998; Izumi et al.
2000; Moir et al. 2000a; Ben-Harush et al. 2009). Also shown are potential posttranslational modifications
(PTMs) and their documented density occurring throughout the monomer where the color intensity is propor-
tional to the probability of finding the PTMs. The most highly occurring PTMs, as shown, are phosphorylation
and ubiquitination, which exhibit an inverse distribution, with phosphorylation more often occurring near and at
the head and tail domains while ubiquitination more frequently found within the central rod domain and
extending toward the Ig fold. The distribution pattern of acetylation is similar to that of ubiquitination, albeit
less frequently occurring. In contrast, O-GlcNAcylation and SUMOylation are sparse and have been found only
on a few residues (Simon and Wilson 2013). (B) A-type lamins (LMNA and LMNC) are the result of alternative
splicing from the LMNA gene, while the major B-type isoforms (LMNB1 and LMNB2) are transcribed from two
different genes. Both LMNA and LMNB1/2 are farnesylated at the cysteine residue of the –CAAX motif by a
farnesyltransferase, followed by the removal of the last three amino acids by means of an AAX endopeptidase and
finally carboxymethylation via carboxyl methyltransferase (Dechat et al. 2008). Lamin B1 and B2 remain
farnesylated, facilitating their anchorage to the nuclear envelope. LMNA undergoes an additional step: removal
of the farnesyl group and the 15 most carboxy-terminal residues by the protease Zmpste24, rendering a fully
functional and mature, lamin A protein (Dechat et al. 2008). (C) Depicts principles of lamin assembly and their
regulation through the cell cycle. Lamin monomers associate in a parallel, head-to-head manner, leading to a
coiled-coil dimer formation—the basic unit for higher-order assembly. As cells enter mitosis, higher-order lamin
filaments localized at the nuclear lamina become phosphorylated by cyclin-dependent kinase 1 (CDK1) and
potentially other kinases triggering the disassembly of the nuclear lamina as lamins depolymerize and become
cytosolic. A-type lamins are found in the cytosol, while depolymerized B-type remain anchored to lipid mem-
branes (Gerace and Blobel 1980). As the cell approaches interphase, lamins are dephosphorylated by protein
phosphatase 1a (PP1a) and are recruited to and reassembled at the reforming NE (Thompson et al. 1997; Dechat
et al. 2010). This reincorporation at the NE is temporally regulated, with B-type lamins organizing to the lamin
first, followed by lamin A and then lamin C networks (Pugh et al. 1997; Shimi et al. 2015; Xie et al. 2016; Wong
et al. 2020). Importantly, and particularly for A-type lamins, a subpopulation of lamins can remain nucleoplas-
mic, due to the persistence of mitotic PTMs such as S22P (Simon and Wilson 2013; Gruenbaum and Medalia
2015; Ikegami et al. 2020; Wong et al. 2020).

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X. Wong et al.
LAMINS AS A SCAFFOLD FOR THE LAMINA
INTERFACE
Lamins interact with a host of nuclear mem-
brane proteins, transcription factors, chromatin
regulators, signaling molecules, splicing factors,
and even chromatin itself to form a nuclear sub-
compartment that is involved in a variety of cel-
lular processes such as the governance of nuclear
integrity, nuclear positioning, mitosis, DNA re-
pair, DNA replication, splicing, mechanotrans-
duction and -sensation, transcriptional regula-
tion, and genome organization. The INM and
the nuclear lamina are interdependent struc-
tures held together by mutual molecular inter-
actions between a myriad of INM proteins and
the underlying lamina meshwork (Fig. 3; Simon
and Wilson 2013; Wong et al. 2014, 2021b).
The protein composition at the nuclear peri-
phery has been profiled in various cell types
using different approaches. Initially, lamin-
associated proteins (LAPs) were identified by
cofractionation in nuclei extracted with high
concentrations of monovalent salts and ionic
detergents (Senior and Gerace 1988; Gerace
and Foisner 1994). More recently, nuclear enve-
lope transmembrane proteins (NETs) have been
identified by mass spectrometry identification
proteins extracted from the NE (Korfali et al.
2012; de Las Heras et al. 2013, 2017; Worman
and Schirmer 2015). Additional LAPs have been
identified by BioID, a technique to biotinylate
proximal proteins, followed by mass spectrom-
etry (Kim et al. 2016; Mehus et al. 2016; Xie et
al. 2016; Wong et al. 2021b). While the terms
may be used interchangeably for the most part, it
is important to note that LAPs are presumed to
interact with lamins, but not necessarily the NE,
since some lamins are nucleoplasmic and, con-
versely, NETs are present in the nuclear enve-
lope, but may not interact with lamins or be at
the INM. Many new tissue-specific NETs have
not been fully characterized.
The LEM (Lap2-Emerin-Man1) domain
family of proteins are LAPs/NETs containing
a LEM domain that binds a conserved metazoan
chromatin protein, barrier to autointegration
factor (BAF), allowing their indirect interaction
with chromatin (Furukawa 1999; Cai et al. 2001,
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2007; Lee et al. 2001; Shumaker et al. 2001; Shimi
et al. 2004; Margalit et al. 2007; Kind and van
Steensel 2014). Mouse and human LEM domain
proteins include LAP2 (lamina-associated poly-
peptide 2), emerin, and MAN1 along with other
LEM and LEM-like proteins (Lin et al. 2000;
Schirmer et al. 2003; Lee and Wilson 2004;
Brachner et al. 2005; Chen et al. 2006; Ulbert
et al. 2006; Simon and Wilson 2013). These
LEM domain proteins, like lamins, are strongly
conserved, reflecting their fundamental roles in
the nucleus. LEM proteins primarily reside in
the INM, but LAP2 has several isoforms, at least
one of which, LAP2α, lacks a transmembrane
domain and is nucleoplasmic; thus, LAP2 can
interact with both nucleoplasmic and INM-as-
sociated lamins (Harris et al. 1994; Berger et al.
1996; Dechat et al. 1998). Nucleoplasmic LAP2α
interacts with nucleoplasmic lamin A (likely
phosphorylated) and has been implicated in
gene activation (Gesson et al. 2016). LEM do-
main proteins are translated into the ER mem-
brane and diffuse into the ONM and then re-
tained in the INM via interactions with lamin
proteins (Holmer and Worman 2001; Wilson
and Foisner 2010; Berk et al. 2013); thus, pertur-
bations of the nuclear lamina can lead to deloc-
alization of these proteins.
Additional well-studied lamin-interacting
proteins include INM proteins such as LBR
and linker of nucleoskeleton and cytoskeleton
complex (LINC) proteins (Fig. 2). LBR is an
eight-pass transmembrane protein localized at
the INM that contains a nucleoplasmic domain
that codes for a sterol reductase. LBR is required
for nuclear shape changes, as seen in neutro-
phils, and is developmentally regulated, with
higher expression in ES and progenitor cells.
LBR has been shown to interact with heterochro-
matin organizers HP1 (heterochromatin protein
1) and PRR14 (proline-rich protein 14), and to
interact with the repressive heterochromatin
modification histone H4 lysine 20 dimethylation
(H4K20me2) (Ye et al. 1997; Polioudaki et al.
2001; Hirano et al. 2012; Dunlevy et al. 2020).
The LINC complex spans the NE and is formed
by interactions between SUN domain proteins of
the INM (SUN1 and SUN2 in somatic cells) and
the KASH domain proteins of the ONM (nes-
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Nuclear Lamina

Microtubules Cytoplasm
Intermediate
F-actin filaments

LINC Nesprin ONM

complex
NPC
SUN protein
PNS
NE INM
Ts Zone 1

NETs
Ts LEM Lamina

LAP
NE
LAP
Zone 2
LAP

HP1 Peripheral heterochromatin/LADs

Peripheral heterochromatin/LADs Zone 3
D s LAD
LAD LA tein
o proteins
proteins pr
Nucleoplasmic lamins

ct

A
iv e p Nucleoplasm
c h r o m a ti n l o o

Figure 3. Structure and complexity at the nuclear periphery. The nuclear lamina serves as an integrative hub for
various aspects of nuclear and cellular functions (Wong et al. 2021b). The lamin meshwork(s) (gray), serves to
maintain nuclear integrity as well as act as a structural scaffold, anchoring a diverse range of proteins and
heterochromatin domains (lamina-associated domains [LADs]) to the nuclear envelope (NE). Lamin-associated
proteins (LAPs) and some nuclear envelope transmembrane proteins (NETs) interact with lamins and chroma-
tin. Relatively more well studied, NETs/LAPs include the components that form the linker of cytoskeleton and
nucleoskeleton complexes (LINCs) (SUN and KASH domain-containing nesprins), LEM domain proteins, and
lamin B receptor (LBR) ( pink), shown above. Additionally, the NE also associates with interphase heterochro-
matin (red chromatin—LADs) providing a structural basis for establishing interphase chromosome topology and
at the same time providing a means for transcriptional gene regulation through repression of genes sequestered at
the periphery. The tethering of chromatin at the nuclear periphery can be achieved via LBR interactions or lamin
A/C. LBR is known to interact directly with chromatin binders (such as Hp1α and PRR14) while A-type lamins
may mediate chromatin contacts through LAPs and chromatin binders and modifiers (orange circles) interacting
with LADs. A recent comparative proteomics study querying the interaction of lamins, LAP2β and LADs, further
resolved the nuclear periphery into three functional zones with respect to chromatin regulation. Zone 1 includes
proteins at the INM/lamina that do not interact with LADs, Zone 2 is comprised of proteins that bind the
INM/lamina network and LADs—the “middlemen,” and Zone 3 contains only proteins associating uniquely
with LADs and chromatin (Wong et al. 2021b).

prins) (Méjat and Misteli 2010; Rothballer and also involved in the cytoplasmic motor-driven
Kutay 2013; Chang et al. 2015; Kim et al. 2015). movement of the nucleus within the cell (Luxton
KASH domain proteins are able to interact with et al. 2010; Wu et al. 2014) and have been impli-
cytoskeletal elements (actin, myosin, and cytosol- cated in gene regulation as well (Kim and Wirtz
ic intermediate filaments); thus, LINCs physically 2015; Tajik et al. 2016). Specific isoforms of nes-
link the nucleoplasm and lamina to the cytoskel- prins are expressed in different cell types (Duong
eton, ultimately connecting to the extracellular et al. 2014) and some KASH-less nesprin isotypes
matrix (ECM) via integrins. It is through these can be found at the INM and interact with lamins
interactions that the nuclear lamina acts as a crit- and emerin directly (Rajgor and Shanahan 2013;
ical mechanosensing and transduction node Kim et al. 2015).
(Lombardi and Lammerding 2011; Osmanagic- As mentioned above, during mitosis, lamins
Myers et al. 2015; Belaadi et al. 2018; Wang et al. are phosphorylated and disassembled. Likewise,
2018; Maurer and Lammerding 2019). LINCs are LAPs and BAFs are also phosphorylated, thus

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X. Wong et al.
leading to loss of LAP–lamin interactions
(Haraguchi et al. 2001; Foisner 2003; Ellenberg
2013). This leads to the vesiculation or move-
ment into the mitotic ER of these INM proteins.
At the onset of anaphase/telophase, these pro-
teins are dephosphorylated and ER/vesicle
membranes are recruited back onto chromatin
to reform the nuclear envelope and subsequently
recruit the lamins. Interestingly, the LEM do-
main proteins emerin and LAP2β appear to in-
teract with condensed chromatin (mediated
through BAF, which is also regulated by mitotic
phosphorylation) and interact with different
chromatin domains than LBR during NE assem-
bly (Haraguchi et al. 2001; Dechat et al. 2004).
Thus, while in the interphase, nuclear lamins
retain the LAP INM proteins and prevent their
redistribution to the ONM and ER, after mitosis
membrane-bound LAPs scaffold on chromatin
and subsequently recruit the nuclear lamins,
highlighting the interdependence of interactions
and the lamina interface.
CELL- AND TISSUE-SPECIFIC INM/LAMINA
PROTEOMES
Many of the proteins that are resident to the pe-
ripheral zone of the nucleus—the lamins, LAPs,
and NETs—are differentially expressed (Figs. 3
and 4; Furukawa and Hotta 1993; Furukawa
et al. 1994; Alsheimer et al. 1999; Schütz et al.
2005a,b; Chen et al. 2006; Korfali et al. 2010,
2012; Jung et al. 2012; Solovei et al. 2013). This
has been highlighted in several proteomic studies
using isolated NE from different cell and tissue
types that have identified many new tissue- and
cell-specific NET proteins. These experiments
uncovered an impressive proteomic diversity of
this cellular compartment. In particular, a com-
parative study across three disparate tissues (liver,
leukocytes, and muscle) revealed that the major-
ity of the 598 NETs displayed distinct expression
profiles between the tissues examined, with only a
modest 16% of these identified NETs being
shared across all three tissue types (Korfali et al.
2012). Other high throughput studies have doc-
umented differential NE proteomes even in less
disparate cell types, such as during T-cell activa-
tion and in addition, using mRNA expression
8 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a040113
analyses, during myogenesis. These types of stud-
ies will undoubtedly continue to identify addi-
tional novel and differential NET proteins and
profiles. How such changes to the nuclear periph-
eral proteome affects cellular process and behav-
ior and how their deregulation would allow the
manifestation of disease phenotypes would be of
particular interest (Wong et al. 2014).
LAMINA-ASSOCIATED DOMAINS (LADs)
The genome is functionally organized, with re-
gions of late-replicating heterochromatin posi-
tioned at the nuclear lamina and at the nucleolar
periphery in most metazoan cells (Cremer and
Cremer 2001). Conversely, more euchromatic re-
gions are positioned in the nuclear interior or
interact with NPC (Buchwalter et al. 2019). Not
surprisingly, lamins have long been implicated in
regulating the three-dimensional (3D) organiza-
tion of chromatin, particularly via these hetero-
chromatin domains found at the nuclear lamina.
3D genome organization and chromatin com-
partments were initially identified and studied
by microscopy and cytological tools using DNA
stains, DNA hybridization techniques such as
fluorescent in situ hybridization (FISH), or elec-
tron microscopy. These early studies led to an
understanding of nonrandom organization of
chromatin, including identification of chromo-
some territories (CTs) and putative regulatory
subdomains within the nucleus, including
the lamina. These studies relied heavily on iden-
tifying spatial relationships between a known se-
quence (or sequences) and a protein compart-
ment (such as the lamina) in the nucleus.
More recently, deep-sequencing-based ap-
proaches have led to genome-wide and molecu-
lar-level understanding of genome organization
and identification of specific DNA sequences and
features that accompany such 3D architecture.
Three different molecular methods and their
derivatives are most routinely used to measure
genome organization: chromatin immunoprecip-
itation (ChIP) (Ma and Zhang 2020), the proxim-
ity-labeling technique DNA adenine methyltrans-
ferase identification (DamID) (Orian et al. 2009),
and chromatin conformation capture methods
such as Hi-C (Lieberman-Aiden et al. 2009; Be-
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Nuclear Lamina

A
Skeletal muscle: Blood
NET9, NET14a, (non-
NET25, NET32, erythrocyte):
NET37, NET39,
Emerin, Man1, Net 9, Net 25, Net 32,
Lamin B1, Lap2, Emerin, Lap2, LBR, Man1,
Lamin A, Lamin C, Lamin B1 (relative levels
LBR, Lamin B2 + not determined). Lamin
muscle-specific NETs A/C, Net 14a, Net 37, Net
39, + blood-specific NETs

Heart:
Net 39, Lamin A, Lamin C,
Liver: Emerin, Net9, Net 14a,
Net 9, Net 37, Lap2, Net 25, Net 32,
Lamin A, Lamin C, Net 37, Lamin B1,
Net14a, Net25, Net32, Lamin B2, Man1, LBR
Lamin B1, Lamin B2, (proteomic studies on
Lap2, Emerin, Man1, hearts not availble)
LBR, NET39 + liver-
specific NETs Fat tissue:
Tissue-specific
proteome speculated
(no comprehensive
proteomic study
performed)
Low High

+ Lamin mutation associated

B Wild-type
with cardiomyopathy

Cardiac-specifc changes in LAD organization

No change in apipose tissue

Wild-type lamin
Cardiomyocyte-specific NET
Cardiomyopathy lamin mutant
Dysfunctional cardiomyocyte-
(Pre) adipocyte-specific NET specific NET

Figure 4. Tissue- and cell-type proteomic diversity at the nuclear lamina. (A) The inferred tissue-specific
expression of nuclear envelope transmembrane proteins (NETs) determined by a transcriptomic analysis
(Chen et al. 2006). For this representation, the proteins were binned into three expression groups for each tissue
type examined: low (green), medium (orange), and high (red). It is clear, even given the small number of proteins
considered here, how different the NE proteome is in divergent cell types. It has been shown for a few cardio-
myopathy lamin mutations that chromatin organization is perturbed in induced pluripotent stem cells derived
cardiomyocytes in the form of gain and loss of lamina-associated domains (LADs), thereby affecting transcrip-
tional output and lineage commitment. (Legend continues on following page.)

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X. Wong et al.

laghzal et al. 2017). ChIP is used to identify chro-
matin domains and binding sites of chromatin
interactors, while DamID and Hi-C directly mea-
sure 3D genome organization, with DamID and
related techniques measuring proximity to a pro-
tein nuclear compartment and Hi-C-related tech-
niques measuring chromatin–chromatin interac-
tions. DamID is most often used to detect
peripheral heterochromatin domains, the so-
called LADs (Greil et al. 2006; Vogel et al. 2007).
Hi-C is used to identify both local and long-range
chromatin interactions (Dekker 2002; Lieberman-
Aiden et al. 2009; Dixon et al. 2012; Phillips-
Cremins et al. 2013; Rao et al. 2014; Belaghzal
et al. 2017), in particular, local self-interacting re-
gions called topologically associated domains
(TADs) and, in active regions of the genome, pro-
moter–enhancer interactions. Of importance to
LAD organization, Hi-C also identifies longer-
range chromosome and genome-wide self-inter-
acting domains: the A (active) and B (inactive)
compartments, with activity state of the compart-
ments being defined via intersections of other data
(such as RNA-seq or chromatin state maps by
ChIP) (Dekker 2002; Lieberman-Aiden et al.
2009; Dixon et al. 2012; Rao et al. 2014). It is
important to note that special care must be taken
in ChIP assays to identify chromatin state and
lamin interactions in heterochromatic regions
since these regions are resistant to traditional
ChIP fragmentation and isolation protocols (Das
et al. 2004; Gesson et al. 2016). An alternative
method to DamID is TSA-seq (tyramide signal
amplification–seq), another proximity-based
method to identify geographic chromatin do-
mains, including LADs (Chen et al. 2018b). These
molecular methods are often combined with ad-
vanced microscopy approaches, including super-
resolution FISH technologies and live cell imag-
ing, to complement and extend the molecular
findings and to map single-cell chromatin confor-
mations and locus positioning in single cells in
situ (Boettiger and Murphy 2020; Kempfer and
Pombo 2020). While genome-wide sequencing
approaches have the advantage of higher resolu-
tion (in base pairs) and numbers of cells pro-
cessed, imaging approaches are inherently single
cell, thus giving an immediate output of cell–cell
variability, but also provide additional contextual
information, such as cellular state and changes
over time. Integration of different data types is
key to understanding genome organization gen-
erally and this also applies to LADs.
As identified by DamID, LAD regions are
large (>100 kb), AT-rich, mostly heterochromatic,
and largely correlate with the inactive B compart-
ment as determined by Hi-C (Fig. 5; Dixon et al.
2012; Rao et al. 2014; Fraser et al. 2015; Robson
et al. 2017). Although CTCF is found at the
boundaries between LADs and non- or inter-
LAD (iLAD) regions (Guelen et al. 2008), thus
demarcating the transition between B and A com-
partments, it is depleted within the LADs them-
selves (Guelen et al. 2008; Harr et al. 2015), sug-
gesting that LADs (and the B compartment) have
a fundamentally different organization than the
CTCF and cohesin-mediated looping structures
found in the active iLAD regions (A compart-
ment). Indeed, depletion of either CTCF or cohe-
sin leads to loss of observable TAD and sub-TAD
organization, but A/B compartmentalization is
largely maintained with only minor changes,
most strikingly the movement of some inactive
regions previously constrained in the A compart-

Figure 4. (Continued) The same mutations, however, have no impact on LAD architecture in hepatocytes and
adipocytes, underscoring the tissue specificity of lamin mutations (Shah et al. 2021). (B) How tissue-specific
proteomes at the nuclear periphery can allow differential susceptibility to lamin mutations. In the top panel, the
expression of a lamin mutation associated with cardiomyopathy disrupts the function of a cardiomyocyte-
specific NET protein (heart shape to broken heart) that may be involved in LAD anchorage, leading to the
loss of LADs at the periphery. In adipocytes, however, a different tissue-specific NET may be involved in LAD
tethering (depicted as lipid droplets), the function of which is not affected by the same lamin mutation and hence
LAD architecture remains unperturbed. It is important to note that such structural reorganization could result
from a mutation in either lamin or the NET protein itself. Crossed-out proteins indicate a documented absence of
these NETs from the indicated tissue. (Figure adapted from Wong et al. 2014.)

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Nuclear Lamina

Chromosome territories

Nuclear envelope
Nuclear lamina
LADs

non-LADs
H3K9me2/3
H3K27me3
CTCF

Chromatin loops

A compartment

B compartment

TADs

DNA

Figure 5. Higher-order genome organization in mammalian cells. Shown is a schematic of the levels of chromatin
folding within the higher-order 3D genome organization. The DNA interacts with histone octamers and aggre-
gates forming nucleosome arrays that are more or less compacted, depending on the histone variants present and
the posttranslational modifications (PTMs) to their amino-terminal tails. The next level of organization is the
formation of topologically associated domains (TADs), which in active chromatin domains are formed by loop
extrusion via cohesin and stabilized by CCCTC-binding factor (CTCF) (Dixon et al. 2012; Rao et al. 2014;
Sanborn et al. 2015). TADs and sub-TADs range from tens of kilobases to megabase-sized and have delimited
boundaries and high rates of interactions inside of these domains. TADs segregate based on their transcriptional
status into active A and inactive B compartments, with A compartments mostly occupying the nuclear interior
and B compartments associated with transcriptionally repressive nuclear domains enriched in histone H3 lysine
9 di- and trimethylation (H3K9me2/3) and histone H3 lysine 27 trimethylation (H3K7me3) at the NE and the
periphery of the nucleoli (Lieberman-Aiden et al. 2009; Harr et al. 2015, 2016; Guelen et al. 2008). It is important
to note that A/B compartments exist even if TADs are depleted, suggesting that segregation into A/B compart-
ments is not driven by TAD architecture (Nora et al. 2017; Schwarzer et al. 2017b). The geographic organization
of the B compartment to the nuclear envelope (NE) aids in the establishment and/or maintenance of interphase
chromosome topology and hence overall genome organization. Moreover, since the nuclear lamina is a tran-
scriptionally repressive compartment, it represents a manipulative model for transcriptional regulation via spatial
organizational changes relative to the lamina. The territorial organization of chromosomes in interphase (chro-
mosome territories [CTs]) constitutes a basic feature of nuclear architecture and these other levels of organization
occur within the context of CTs (Cremer and Cremer 2010). (Figure based on data in Maeshima et al. 2020.)

ment to the B compartment (Nora et al. 2017; 2019). It remains unclear, however, whether
Schwarzer et al. 2017a). Thus, the genome re- LADs remain geographically positioned at
mains partitioned, even if reconfigured (Nora the nuclear lamina in the absence of CTCF or
et al. 2017; Schwarzer et al. 2017b; Falk et al. cohesin.

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X. Wong et al.
GEOGRAPHIC ORGANIZATION OF LADs
IS REGULATED BY CHROMATIN STATE
LADs are enriched in histone H3 lysine 9 di- and
trimethylation (H3K9me2/3) and this modifica-
tion is also required for LAD recruitment to and
maintenance at the nuclear lamina (Guelen et al.
2008; Towbin et al. 2012; Harr et al. 2015). In
mammals, proline-rich protein 14 (PRR14) has
been shown to anchor these regions to the lamina
through its interactions with heterochromatin
protein 1 (HP1), a chromodomain protein that
binds H3K9me3 (Poleshko and Katz 2014; Dun-
levy et al. 2020), while in Caenorhabditis elegans
this function is carried out by the INM-bound
chromodomain protein CEC-4 (Towbin et al.
2012; Gonzalez-Sandoval et al. 2015; Gonzalez-
Sandoval and Gasser 2016; Harr et al. 2016, 2020;
Bian et al. 2020). Intriguingly, heterochromatic
regions have been shown to accrete due to phase
separation directed by HP1α, and the organiza-
tion of LADs at the lamina likely depends upon
such biophysical forces (Larson et al. 2017; Strom
et al. 2017; Falk et al. 2019). In particular, bio-
physical models predict that, in the absence of an
active constraint at the nuclear lamina, LADs
would form large clusters in the nucleoplasm
(Falk et al. 2019). This is supported by studies
showing that in cells lacking lamin A/C and
LBR (either naturally or engineered) heterochro-
matin configuration is inverted (Solovei et al.
2013). Thus, the heterochromatic nature of
LADs leads to their separation from euchromatic
regions, but other forces and interactions are like-
ly at play in geographically organizing these re-
gions to the lamina. There is a less clear role for
the facultative heterochromatin modification his-
tone H3 lysine 27 trimethylation (H3K27me3) in
LAD organization, since this modification is
found mostly outside of LADs, but is enriched
at LAD borders (Guelen et al. 2008; Harr et al.
2015) and necessary to target an inserted test
locus to the lamina in coordination with
H3K9me2/3 (Harr et al. 2015). In contrast, in
C. elegans, H3K27me3 modifications seem to
be dispensable for driving peripheral localization,
but there is a second pathway for lamina locali-
zation independent of Cec-4/H3K9me3 anchor-
ing (Towbin et al. 2012). In a clever screen using
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cec-4 null worms, this second pathway was dis-
covered to be a sequestration of euchromatin
away from the lamina (Cabianca et al. 2019). In
this case, the delocalization of CBP/p300 causes
aberrant H3K27Ac to replace H3K27me3, sug-
gesting that sequestration of active chromatin
modifiers is a driving force for tethering of het-
erochromatin to the lamina in differentiated cells.
Similarly, in a recent study in mouse T-cells in
which a LAD border region at the T-cell receptor
(TCR) locus was deleted, invading H3K27ac was
found to drive an enhancer region away from
the nuclear lamina and subsequently led to al-
tered enhancer–promoter interactions (Chen
et al. 2018a). The role of histone H4 lysine 20
dimethylation (H4K20me2), a repressive chro-
matin mark bound by the tudor domain of LBR
(Hirano et al. 2012), in LAD regulation and
organization remains unclear. H4K20me2 has
a wide genome distribution with enrichment
on centromeric and telomeric chromatin and
does not appear to be particularly enriched on
LADs (Mattout et al. 2015). However, this mod-
ification does seem to play a role in LAD regu-
lation/organization under certain conditions,
particularly senescence and in particular lami-
nopathies (Shumaker et al. 2006; Barski et al.
2007; Bártová et al. 2008; Mattout et al. 2015;
Nelson et al. 2016). Taken together, these stud-
ies suggest a complex interplay between chro-
matin state and chromatin-binding proteins in
the separation and organization of LADs to the
periphery.
GENE REGULATION IN LADs
LAD regions contain relatively few genes, but
are, conversely, enriched in developmental and
lineage-specific genes, leading to the hypothesis
that the epigenetic state of these regions is tied
to both organization and developmental con-
trol of gene expression (Guelen et al. 2008;
Peric-Hupkes et al. 2010; Bian et al. 2013;
Harr et al. 2015). Indeed, early studies of regu-
lation of individual genes by the nuclear lamina
focused on developmentally regulated gene loci,
such as the immunoglobulin heavy chain locus
(Igh) in B-cell development (Kosak et al. 2002),
the β-globin locus in erythroid development
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(Bian et al. 2013), and MyoD in muscle devel-
opment (Yao et al. 2011) among others. These
early studies pointed to the dynamic nature of
loci associated with (and presumably regulated
by) the nuclear lamina during development,
but it was not until genome-wide mapping
through DamID that the shifting LAD organi-
zation, chromatin, and expression landscape
could be fully appreciated. LADs are dynamic
between cell states and in a simplistic view can
be divided into constitutive or facultative LADs,
cLADs, and fLADs, respectively (Peric-Hupkes
et al. 2010; Meuleman et al. 2012; van Steensel
and Belmont 2017). cLADs are LADs that re-
main irrespective of cell type, while fLADs re-
organize between cell types or developmental
stages. The majority of LADs do not change
between individual cell types, although 70% of
LADs are fLADs; thus, reorganization is re-
stricted by cell type. fLADs are more gene
rich and in cell types where they undergo reor-
ganization away from the lamina, genes in these
regions are activated or poised for activation
(Peric-Hupkes et al. 2010). Even within a given
cell type or population there is some cell–cell
heterogeneity in LAD organization, as detected
by low-resolution, single-cell DamID, with
more gene-dense LADs displaying greater fluc-
tuations in their association with the lamina,
implying that these disruptions may be due to
differential gene usage between cells (Kind et al.
2015). A level of heterogeneity in reorganizing
to the lamina after cell division has also been
noted, with some LADs appearing to become
nucleolar-proximal in the daughter cells, al-
though there is some expected overlap between
nucleolar-associated domains (NADs) and
LADs given the invaginations of nuclear lamins
at nucleoli noted in many cell types (Cremer and
Cremer 2001; Legartová et al. 2014; Padeken and
Heun 2014).
In addition to LAD heterogeneity between
cells, it has been documented that different pro-
moters respond differently to integration into a
LAD and to different environments within a
LAD. Early ectopic lamina tethering experiments
suggested that recruitment to the nuclear lamina
reduces expression of the tethered locus. In one
report, an integrated reporter gene in mouse cells
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Nuclear Lamina
showed a two- to threefold reduction in expres-
sion after tethering using a truncated emerin to
tether a lac operator array (lacO) (Reddy et al.
2008). A similar study, using Lap2β to target a
lacO array in a human cell line, found only a
minimal reduction in the recruited reporter
gene expression, while a subset of endogenous
flanking genes on the same chromosome did
show reduced expression (Finlan et al. 2008). In
Drosophila, the tethering of two lacO tagged re-
porter genes by Dme/LamC to the nuclear lamina
caused substantial repression, but the level of re-
pression was integration site and reporter gene
dependent (Dialynas et al. 2010). These early re-
sults suggested that recruitment to the lamina
could cause repression, but that this repression
was variable depending upon local chromatin
context and different promoters. A more recent
study sought to investigate exactly this question
and found that upon integration into LADs some
promoters are more sensitive to the more repres-
sive environment and are almost universally
repressed, while other promoters can “escape”
silencing within LAD regions (Leemans et al.
2019). These escapers were generally less sensitive
repressive domains, particularly H3K27me3. All
promoters showed some variation in regulation
by LADs and less repressed promoters were
found to reside in more weakly (and perhaps
transiently) lamina-bound regions within LADs
(Leemans et al. 2019). Thus, even though LADs
are generally repressive, genes respond differently
depending upon promoter type and local LAD
context.
ROLE OF TRANSCRIPTION FACTORS IN LAD
ORGANIZATION
While both lamins and chromatin are important
for organization of LADs to the nuclear lamina,
there is some evidence that transcription factors
and machinery may be more directly involved in
peripheral localization (and regulation) of genes
at the lamina. Several transcription factors have
been found to interact with lamins and/or
lamin-interacting proteins, and some of these
have been proposed to be more directly involved
in organizing specific loci to the lamina. One
study found that sequences from two different
13
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X. Wong et al.
LAD-regulated loci enriched in GA dinucleo-
tides were able to drive an ectopic region to
the lamina (Zullo et al. 2012). This is interesting
given that GA dinucleotides are not enriched in
the relatively AT-rich LADs (Guelen et al. 2008).
These motifs were found to bind a cell-type-spe-
cific transcription factor (ZBTB7B, also known
as THPOK) in complex with a histone deacety-
lase (HDAC3), and an inner nuclear membrane
protein (LAP2β) to mediate de novo interac-
tions with the nuclear lamina. Both ZBTB7B
and HDAC3 were also found to be important
for myogenesis and in regulating myogenic
genes and their organization to the lamina
(Poleshko et al. 2017), suggesting that specific
transcription factor complexes can regulate lam-
ina interactions, potentially directly. ZBTB7B
features a BTB–POZ domain that recruits Poly-
comb repressive complex 2 (PRC2) to chroma-
tin, thereby initiating trimethylation of histone
H3 on lysine 27 (H3K27me3) (Boulay et al.
2012). Interestingly, there are numerous BTB-
POZ domain transcription factors that are ex-
pressed in a cell-type-specific manner, and these
have been found to both activate and repress
gene expression and to interact with HDAC3.
HDAC3 itself, which interacts with numerous
transcription factor complexes, has been shown
in independent studies to interact with both
LAP2β and emerin (Somech et al. 2005; Dem-
merle et al. 2012). Whether this complex of
ZBTB7B, HDAC3, and LAP2β initiates locus
interaction at the lamina or simply maintains a
heterochromatin state is unclear. Other studies
suggest that altered chromatin state, including
both H3K9me2/3 and H3K27me3, drive lamina
association (Bian et al. 2013, 2020; Kind et al.
2013; Harr et al. 2015). Taken together, these
findings suggest that the epigenetic state may
be the ultimate factor in determining organiza-
tion to the lamina. Lamina-associating sequenc-
es may recruit repressive transcriptional com-
plexes to promote a local chromatin signature
favorable for lamina association. While at the
lamina, these complexes would then maintain
or reinforce this repressive state, in agreement
with studies showing that integration of pro-
moter sequences into LADs leads to their re-
pression.
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LAD ORGANIZATION HELPS ENFORCE
CHROMATIN AND GENE EXPRESSION
PROGRAMS
If chromatin state drives lamin association, is as-
sociation with the nuclear lamina simply a by-
product of this chromatin state and biophysical
properties? It is difficult to tease apart the role
that chromatin state itself versus organization to
the lamina plays. As discussed previously, re-
cruiting inserted reporter genes to the lamina is
able to repress some genes, depending on pro-
moters and integration site (Finlan et al. 2008;
Reddy et al. 2008). In addition, biophysical mod-
eling shows that in the absence of nuclear periph-
ery “tethers,” heterochromatin will not organize
to the lamina, but is instead predicted to collapse
into the center of the nucleus and form an “in-
verted” type of chromatin organization (Falk
et al. 2019). This implies that there are active
mechanisms to organize LADs to the nuclear
lamina. In support of this, several studies have
implicated A-type lamins as especially important
for the geographical organization of LADs to the
lamina in differentiated cells (Solovei et al. 2013;
Harr et al. 2015; Zheng et al. 2018). In particular,
the predicted inverted chromatin organization is
noted in the absence of both A-type lamins and
LBRs (Solovei et al. 2013); thus, chromatin orga-
nization to the lamina is not the default. But is
there evidence that loss of lamin association af-
fects gene regulation—that such localization is
itself important? In C. elegans, a global reduction
of lamin–chromatin interactions through deple-
tion of the chromobox protein CEC-4, which is
required for lamina association, resulted in
up-regulation of only one single gene, while de-
pletion of H3K9 methylation caused widespread
disruption (Gonzalez-Sandoval et al. 2015).
From this experiment, one could conclude that
organization of chromatin into LADs at the lam-
ina is not important for gene repression (al-
though there is a second non-CEC-4-dependent
anchoring pathway that confounds these results
(Cabianca et al. 2019). However, loss of CEC-4
did impair induced differentiation into muscle
cells, reminiscent of mouse studies, in which
the effect of loss of lamins is seen later in muscle
differentiation (Sullivan et al. 1999). In addition,
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several developmentally regulated tissue-restrict-
ed NETs have been shown to cause reorganiza-
tion of lineage-specific genes and altered expres-
sion when ectopically expressed, suggesting that
these proteins directly influence organization and
regulation (de Las Heras et al. 2017). In cells in-
duced to undergo senescence, alterations in LAD
organization were noted, including altered
chromatin state outside and inside of LADs, par-
ticularly an encroachment across boundaries,
suggesting a “blurring” of chromatin domains
(Shah et al. 2013). This disorganization and dys-
regulation could be mimicked by acute depletion
of lamin B1, suggesting that, unlike ES cells, more
differentiated cells may rely on the geographical
organization of heterochromatin to the lamina to
maintain a cell-type-specific chromatin land-
scape. This is in agreement with the idea of
LAD organization functioning as a mechanism
to maintain a cell-type-specific epigenetic state;
some cell types and states will be more sensitive to
disruption of LAD organization.
DYNAMIC ORGANIZATION OF LADs
THROUGH THE CELL CYCLE
Interphase genome organization, including LAD
and lamin organization, is ablated during mitosis
and re-established after mitosis (Burke and Ellen-
berg 2002; Salina et al. 2003; Kind et al. 2013;
Naumova et al. 2013; Kind and van Steensel
2014; Gibcus et al. 2018; Luperchio et al. 2018).
Several studies have suggested that A-type lamins
organize to the reforming nuclear envelope with
different kinetics, although there is some discrep-
ancy on how lamin A and C might differ in their
timing of association (Pugh et al. 1997; Moir et al.
2000b; Vaughan et al. 2001; González-Cruz et al.
2018). Recent work has not only highlighted how
chromosomes condense into their mitotic con-
figuration, but also how these regions reorganize
into their interphase configuration postmitosis
(Gibcus et al. 2018; Zhang et al. 2019). These
studies focused on chromatin configuration as
measured by Hi-C and it is notable that chroma-
tin A/B compartment organization precedes
TAD organization, and that compartmentaliza-
tion intensifies as the cells proceed further into
interphase. Given that LADs are highly enriched
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Nuclear Lamina
in the B compartment, such findings highlight a
dynamic process of organization of LADs post-
mitosis. In a clever study using an antibody var-
iant of DamID technology called pA-DamID on
synchronized cells, dynamics of LAD organiza-
tion after mitotic exit were revealed (van Schaik
et al. 2020). LADs organize to the nuclear lamina
in early G1, with more telomere-proximal LADs
interacting first, followed by more centromere-
proximal LADs. Because these studies were
done in human cells, this stepwise association
of different chromosomal positions suggests
that the orientation of the chromosomes postmi-
tosis influences LAD organization to the lamina.
These associations generally increase as cells pro-
gress further into interphase, in agreement with
the increased A/B compartmentalization noted
in the earlier Hi-C studies. The relationship be-
tween LAD organization and lamin reorganiza-
tion after mitosis remains to be determined.
LAMINOPATHIES
Disruption of the unique protein environment
of the nuclear lamina often leads to disease
(Table 1). The diseases that result from mutations
in LMNA, or other NET or LAP proteins that
heavily interact with lamins, are collectively
termed “laminopathies” or “envelopathies.” Be-
cause of differential expression of lamins during
development and in different cell types along with
the complex and cell-type-specific interactomes
(NETs and LAPs), laminopathies display a wide
breadth of phenotypes. Most laminopathies are
autosomal dominant and generally cause late-
onset degeneration of mesenchymal-derived cells
(Wong et al. 2021a). Nearly 500 disease-causing
mutations have mapped to the LMNA gene, each
with its own specific phenotype, and manyof these
mutations are dominant. A variety of models have
been suggested to explain the variety of cell- and
tissue-specific phenotypes. Indeed, it appears that
disruption of lamins or lamin-binding proteins
affect numerous cellular functions, depending
upon the particular mutation and cell type, includ-
ing perturbations in mechanosensation and resil-
ience, DNA repair, signaling pathways, interac-
tions with specific transcription factor, altered
interactions with NETs/LAPs, altered chromatin
15
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Harbor Laboratory Press

X. Wong et al.

Table 1. Diseases of the nuclear periphery

Gene Disease/anomaly Other notes
Primary laminopathies
LMNA Autosomal-dominant form of Emery– Affects striated muscle tissues
Dreifuss muscular dystrophy (AD-
EDMD)
Dilated cardiomyopathy (DCM)
Limb-girdle muscular dystrophy 1B
(LMG1B).
Peripheral neuropathy (R298C), a
recessive form of Charcot-Marie-
Tooth disease (AR-CMT2A)
Dunnigan-type familial partial Affects fat distribution and skeletal
lipodystrophy (FPLD2) development
Mandibuloacral dysplasia (MAD)
Hutchinson–Gilford progeria Premature aging
syndrome (HGPS)
Atypical Werner’s syndrome
LMNB1 Adult-onset autosomal-dominant Neural
leukodystrophy (ADLD)
Ataxia telangiectasia
Gene Function Disease/anomaly
Secondary envelopathies
Emerin (EMD) NE associated, may regulate β-catenin X-linked Emery–Dreifuss muscular
nuclear entry and MKL1 nuclear dystrophy
localization
Man1 (LEMD3) Regulates TGF-β signaling by Buschke–Ollendorff syndrome; excessive
modulating Smad phosphorylation bone nodule formation, required for
development of the vascular system
Lap1/Traf3/TOR1AIP1 Interacting protein with Torsin, Myopathy exacerbated by EMD loss
LULL1, and emerin
LEMD2/Net25 Chromatin organization MAP/AKT Homozygote nulls embryonic lethal
signaling progeroid; symptoms result from
missense mutations
Lap2 Chromatin organization, telomere Dilated cardiomyopathy, reduced
maintenance epidermal proliferation, ameliorates
LMNA-induced MD/DCM
Torsin AAA+ATPAse interacts closely with DYT dystonia in CNS, steatohepatitis
Lap1
Lamin B receptor (LBR) Multifunctional-reduced sterol Pelger–Huët anomaly, Greenberg
reductase activity, heterochromatin dysplasia
organization
Nesprin1 (SYNE1) LINC complex tethers nucleus to Limb girdle muscular dystrophy; ARCA1
cytoskeleton cerebellar ataxia required for nuclear
migration during CNS development
Nesprin2 (SYNE2) LINC complex tethers nucleus to EDMD variants required for nuclear
cytoskeleton migration during CNS development
Nesprin/Kash4 Interacts with MT motor proteins Required for nuclear positioning in
cochlear hair cells, mutations result in
deafness
Continued

16 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a040113
Downloaded from http://cshperspectives.cshlp.org/ at SEOUL NATL UNIV. on September 11, 2023 - Published by Cold Spring
Harbor Laboratory Press
Table 1. Continued
Gene Disease/anomaly
SUN1 Anchors LINC complex to the INM,
regulates miRNA synthesis during
muscle regeneration
BANF1 Postmitotic nuclear reassembly,
chromatin organization
Data adapted from Wong and Stewart (2020).
state, and genome organization, none of which are
mutually exclusive (Mewborn et al. 2010; Osma-
nagic-Myers et al. 2015; Vadrot et al. 2015; Wor-
man and Schirmer 2015; Perovanovic et al. 2016;
Le Dour et al. 2017; Briand and Collas 2018; Bian-
chi et al. 2018; and reviewed in Wong et al. 2021a).
CONCLUDING REMARKS
The multiple functions of lamins and the nuclear
lamina make it very difficult to assess the impact
of lamina abnormalities on diseases initiated by
LMNA or NET mutations. In laminopathies,
both gene dysregulation and the loss of nuclear
integrity seem to play a role in observed pheno-
types. Since this interface controls both the me-
chanical “fitness” of the nucleus (through
LINCs, lamins, and heterochromatin scaffold-
ing) as well as genome regulation, it will be in-
teresting to determine how mechanical force re-
lates to genome organization. In addition, while
it is clear that lamina association frequently re-
presses genes, how LADs are mechanistically
maintained at and/or reorganized to the nuclear
periphery during interphase and particularly
during mitotic exit are only recently getting un-
raveled. Systematic study of how candidate
factors (including lamin isotypes, chromatin
interactors, NETs, and mechanical inputs) influ-
ence LAD and lamina organization during mi-
tosis to G1 may help provide more definitive
answers on the role of these regulators in lamina
and LAD organization and regulation, and the
consequences of their disruption in disease.
ACKNOWLEDGMENTS
Funding sources were NIHR01GM132427 to
K.L.R. and A.J.M-P. and NIH R25GM109441
to A.J.M.-P.
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a040113
Nuclear Lamina
Other notes
Ameliorates LMNA-induced DCM/MD,
missense mutations associated with
MD
Nestor–Guillermo progeria
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The Nuclear Lamina

Xianrong Wong, Ashley J. Melendez-Perez and Karen L. Reddy

Cold Spring Harb Perspect Biol published online August 16, 2021

Subject Collection The Nucleus

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