Sun_Yang2021_Morphological

“Experience and sleep-dependent synaptic plasticity: from structure to activity”

With sleep, activity-mediated synaptic plasticity genes expression decrease: arc, cfos, bdnk,
homer 1a
66. Cirelli C, Gutierrez CM, Tononi G. 2004 Extensive anddivergent effects of sleep and wakefulness on braingene
expression.Neuron41,35–43. (doi:10.1016/s0896-6273(03)00814-6)

67. Mackiewicz Met al.2007 Macromoleculebiosynthesis: a key function of sleep.Physiol.Genomics31, 441–457.

(doi:10.1152/physiolgenomics.00275.2006

69. Vecsey CGet al.2012 Genomic analysis of sleepdeprivation reveals translational regulation in thehippocampus.Physiol.
Genomics44, 981–991.(doi:10.1152/physiolgenomics.00084.2012)

With REM sleep, synaptic plasticity-related gene expression increase: cAMP, ERK activity, MAPK
activity, CREB phosphorylation, zif-268
71. Luo J, Phan TX, Yang Y, Garelick MG, Storm DR.2013 Increases in cAMP, MAPK activity, and CREBphosphorylation
during REM sleep: implications forREM sleep and memory consolidation.J. Neurosci.33, 6460–6468.
(doi:10.1523/JNEUROSCI.5018-12.2013)

72. Ribeiro S, Goyal V, Mello CV, Pavlides C. 1999 Braingene expression during REM sleep depends on priorwaking
experience.Learn. Mem.6, 500–508.(doi:10.1101/lm.6.5.500)

73. Ribeiro S, Mello CV, Velho T, Gardner TJ, Jarvis ED,Pavlides C. 2002 Induction of hippocampal long-term potentiation
during waking leads to increasedextrahippocampalzif-268expression during ensuingrapid-eye-movement sleep.J.
Neurosci.22,10 914–10 923. (doi:10.1523/JNEUROSCI.22-24-10914.2002)

No discussion of methods

Huang&Sigrist2021_Plasticity

“Presynaptic and postsynaptic long-term plasticity in sleep homeostasis”

SIK3

Splice mutation in mice promoted NREM sleep

27. FunatoH,MiyoshiC,FujiyamaT,KandaT,SatoM,WangZ,MaJ,NakaneS,TomitaJ,IkkyuAetal.:Forward-
geneticsanalysisofsleepinrandomlymutagenizedmice.Nature2016,539:378-383.

brp (Drosophila)

Increasing gene copy provoked sleep in a dose-dependent manner (two to three to four
times). Reducing gene copy only decreased sleep in short sleep mutants.
24.
HuangS,PiaoC,BeuschelCB,GotzT,SigristSJ:PresynapticactivezoneplasticityencodessleepneedinDrosophila.CurrBiol2020,30:107
7-1091.e5http://dx.doi.org/10.1016/j.cub.2020.01.019
Ode_Ueda2020

“Phosphorylation Hypothesis of Sleep”

The kinase genes referenced were mainly studied comparing mice with or without that gene.
The rest of the review focuses on the proteins/protein interactions that gene encodes.

Camk2a/Camk2b

Embryonic knockout (with CRISPER/Cas9) in mice led to decrease in sleep duration

Tatsuki, F., Sunagawa, G. A., Shi, S., Susaki, E. A., Yukinaga, H., Perrin, D., et al.(2016). Involvement of Ca(2+)-dependent
hyperpolarization in sleep durationin mammals.Neuron90, 70–85. Doi: 10.1016/j.neuron.2016.02.032

SIK3

Screening of >8000 mice identified a genetic difference in a sleepy mice with an exon
skipped in SIK3. This exon is a phosphorylation site on SIK3 (S551). This phosphorylation
site is inferred to reduce/regulate the activity of SIK3.
Funato, H., Miyoshi, C., Fujiyama, T., Kanda, T., Sato, M., Wang, Z., et al. (2016).Forward-genetics analysis of sleep in randomly
mutagenized mice.Nature539,378–383. doi: 10.1038/nature20142

Point mutation of S551A in mice (using CRISPR mediated embryonic introduction)

reproduced sleepiness
Honda, T., Fujiyama, T., Miyoshi, C., Ikkyu, A., Hotta-Hirashima, N., Kanno,S., et al. (2018). A single phosphorylation
site of SIK3 regulates daily sleepamounts and sleep need in mice.Proc. Natl. Acad. Sci. U.S.A.115, 10458–10463.doi:
10.1073/pnas.1810823115

ERK1/ERK2

In mice, embryonic knockout of ERK1—and conditional knockout of ERK2 in cortical

regions—led to a decrease in NREM sleep duration
Mikhail, C., Vaucher, A., Jimenez, S., and Tafti, M. (2017). ERK signalingpathway regulates sleep duration
through activity-induced gene expressionduringwakefulness.Sci. Signal.10:eaai9219.doi:10.1126/scisignal.aai9219

Sleep inducing substances

Adenosine A1 receptor: knockout impairs increase of slow wave activity without

affecting total sleep
Bjorness, T. E., Kelly, C. L., Gao, T., Poffenberger, V., and Greene, R. W.(2009). Control and function of the homeostatic
sleep response by adenosineA1 receptors.J. Neurosci.29, 1267–1276. doi: 10.1523/JNEUROSCI.2942-08.2009

Adnesoine A2 receptor: knockout dimisnishes wake-proimoting effect of caffeine but no

significant effect on normal sleep
Huange, Z. L., Qu, W. M., Eguchi, N., Chen, J. F., Schwarzschild, M. A., Fredholm,B. B., et al. (2005). Adenosine A2A, but not A1,
receptors mediate the arousaleffect of caffeine.Nat. Neurosci.8, 858–859. doi: 10.1038/nn1491

TNF-alpha: knockout increases slow wave activity during NREM, but no affect on total
sleep duration
Fang, J., Wang, Y., and Krueger, J. M. (1997). Mice lacking the TNF 55 kDareceptor fail to sleep more after TNFalpha
treatment.J. Neurosci.17, 5949–5955.doi: 10.1523/jneurosci.17-15-05949.1997

Kaushal, N., Ramesh, V., and Gozal, D. (2012). TNF-alpha and temporal changes insleep architecture in mice exposed to sleep
fragmentation.PLoS One7:e45610.doi: 10.1371/journal.pone.0045610
Transcription factor Dgb

Expression is suppressed in sleep-deprived rats

Cirelli, C., Gutierrez, C. M., and Tononi, G. (2004). Extensive and divergenteffects of sleep and wakefulness on brain gene
expression.Neuron41, 35–43.doi: 10.1016/s0896-6273(03)00814-6

And also in cultured cortical neurons stimulated by wake-mimicking chemicals

Mikhail, C., Vaucher, A., Jimenez, S., and Tafti, M. (2017). ERK signalingpathway regulates sleep duration
through activity-induced gene expressionduringwakefulness.Sci. Signal.10:eaai9219.doi:10.1126/scisignal.aai9219

Protein phosphatase 1 regulatory subunit 9B (Ppp1r9b)

Knockout in mice reduced sleep duration (analyzed by piezoelectric-sensory based

activity reading)
Jan, M., O’Hara, B. F., and Franken, P. (2020). Recent advances in understandingthe genetics of sleep.F1000Res9:214. doi:
10.12688/f1000research.22028.1

Calcineurin and sarah

In Drosophila, knockout of this Ca2+/calmodulin-dependent protein phosphatase and its

regulator Sarah caused a decrease in sleep duration
Nakai, Y., Horiuchi, J., Tsuda, M., Takeo, S., Akahori, S., Matsuo, T., et al. (2011).Calcineurin and its regulator sra/DSCR1 are
essential for sleep inDrosophila.J. Neurosci.31, 12759–12766. doi: 10.1523/JNEUROSCI.1337-11.2011

Tomita, J., Mitsuyoshi, M., Ueno, T., Aso, Y., Tanimoto, H., Nakai, Y., et al.(2011). Pan-neuronal knockdown of
calcineurin reduces sleep in the fruitfly,Drosophila melanogaster.J. Neurosci.31, 13137–13146. doi:
10.1523/JNEUROSCI.5860-10.2011
Abel_2020_Epigenome

“Sleep Deprivation and the Epigenome”

Dnmt3a1/Dnmt3a2 (enzymes related to DNA methylation)

In mice following acute SD, gene expression increases. Also, hydroxymethylation

increased at 3’UTR
Massart, R., Freyburger, M., Suderman, M., Paquet, J., El Helou, J., Belanger-Nelson, E., et al. (2014). The genome-wide
landscape of DNA methylationand hydroxymethylation in response to sleep deprivation impacts on synapticplasticity
genes.Transl. Psychiatry4:e347. doi: 10.1038/tp.2013.120

Methlyated genes with SD

PER1 predicted enhancer region, CRY1 promoter region hypermethylated in sleep-

deprived adipose tissue samples. No change in gene expression.
Cedernaes, J., Osler, M. E., Voisin, S., Broman, J. E., Vogel, H., Dickson, S. L., et al.(2015). Acute sleep loss induces tissue-
specific epigenetic and transcriptionalalterations to circadian clock genes in men.J. Clin. Endocrinol. Metab.100,E1255–E1261.
doi: 10.1210/JC.2015-2284

Hypermethylation of CRY2, hypomethylation of CLOCK in long-term night-shift workers

Zhu, Y., Stevens, R. G., Hoffman, A. E., Tjonneland, A., Vogel, U. B., Zheng, T.,et al. (2011). Epigenetic impact of long-term
shiftwork: pilot evidence fromcircadian genes and whole-genome methylation analysis.Chronobiol. Int.28,852–861. doi:
10.3109/07420528.2011.618896

SCD1 (enzyme in fatty acid desaturation) increased DNA meth near transcription start
site following SD in male blood
Skuladottir, G. V., Nilsson, E. K., Mwinyi, J., and Schiöth, H. B. (2016). One-nightsleep deprivation induces changes in the DNA
methylation and serum activityindices of stearoyl-CoA desaturase in young healthy men.Lipids Health Dis.15:137. doi:
10.1186/s12944-016-0309-1

Dlg4 increased DNA meth in an intron following acute SD in miceincreasing its

expression
Massart, R., Freyburger, M., Suderman, M., Paquet, J., El Helou, J., Belanger-Nelson, E., et al. (2014). The genome-wide
landscape of DNA methylationand hydroxymethylation in response to sleep deprivation impacts on synapticplasticity
genes.Transl. Psychiatry4:e347. doi: 10.1038/tp.2013.120

ING5 decreased DNA meth upstream gene following acute SD in male

blooddecreasing expression
Doyon, Y., Cayrou, C., Ullah, M., Landry, A. J., Côté, V., Selleck, W., et al.(2006). ING tumor suppressor proteins are critical
regulators of chromatinacetylation required for genome expression and perpetuation.Mol. Cell21,51–64. doi:
10.1016/j.molcel.2005.12.007

Acytelated genes with SD

BDNF promoter IV has reduced occupancies of acetylated histones in hippocampus of

SD rats
Duan, R., Liu, X., Wang, T., Wu, L., Gao, X., and Zhang, Z. (2016).Histone acetylation regulation in sleep deprivation-induced
spatial memoryimpairment.Neurochem. Res.41, 2223–2232. doi: 10.1007/s11064-016-1937-6

Reduced BDNF transcription and translation along with decreased CREB expression after
prolonged SD in rats
 Guzman-Marin, R., Ying, Z., Suntsova, N., Methippara, M., Bashir, T.,Szymusiak, R., et al. (2006). Suppression of
hippocampal plasticity-relatedgene expression by sleep deprivation in rats.J. Physiol.575, 807–819.doi:
10.1113/jphysiol.2006.115287

Non-coding RNAs

Deletion of lncRNA 116HG causes dysregulation of circadian genes Clock, Cry1, and Per2
Powell, W. T., Coulson, R. L., Crary, F. K., Wong, S. S., Ach, R. A.,Tsang, P., et al. (2013). A Prader-Willi locus lncRNA cloud
modulatesdiurnal genes and energy expenditure.Hum. Mol. Genet.22, 4318–4328.doi: 10.1093/hmg/ddt281

Jan_Franken2020

“Recent advances in understanding the genetics of sleep”

Drosophila

Shaker – loss-of-function mutations caused flies to sleep very little (found with random
mutations and identification based on phenotype)
12. Cirelli C, Bushey D, Hill S, et al.: Reduced sleep in Drosophila Shakermutants.Nature. 2005; 434(7037): 1087–92

Sleepless – regulated Shaker, promoted sleep

13. Koh K, Joiner WJ, Wu MN, et al.: Identification of SLEEPLESS, a sleep-promoting factor.Science. 2008; 321(5887): 372–6.

Nemuri – by phenotyping 12,000 fly lines for sleep duration, which induced sleep in
adults when overexpressed
10. Toda H, Williams JA, Gulledge M, et al.: A sleep-inducing gene, nemuri, links sleep and immune function in
Drosophila.Science. 2019; 363(6426): 509–15.

80 genes related to Egfr, Wnt, Hippo, and Mapk signaling pathways identified between
differences in sleep duration in a genetic reference population (GRP)

64. Harbison ST, Serrano Negron YL, Hansen NF, et al.: Selection for long and
short sleep duration in Drosophila melanogaster reveals the complex genetic
network underlying natural variation in sleep.PLoS Genet. 2017; 13(12):
e1007098

Mice

Sik3 – increase homeostatic sleep drive, increase time in NREM. (Random mutation
experiment and identification based on phenotype)
16. Honda T, Fujiyama T, Miyoshi C, et al.: A single phosphorylation site of SIK3 regulates daily sleep amounts and sleep need
in mice.Proc Natl Acad Sci U S A.2018; 115(41): 10458–63.

Nalcn – missense mutation reduced time spent in REM (voltage-independent and non-
selective cation channel)

Cacna1a – point mutation reduced wakefulness by about 70 min/day (voltage-

dependent calcium channel)
 19. Miyoshi C, Kim SJ, Ezaki T, et al.: Methodology and theoretical basis of forward genetic screening for sleep/wakefulness in
mice.Proc Natl Acad Sci U S A. 2019; 116(32): 16062-7

Ppp1r9b, Pitx3, Ap4e1, Myh1 – affected time spent asleep; found during IKMC efforts of
knocking out each protein-coding gene while IMPC determines phenotypic
consequences
26. Skarnes WC, Rosen B, West AP, et al.: A conditional knockout resource for the genome-wide study of mouse gene
function.Nature. 2011; 474(7351): 337–42.

Chrm1, Chrm3 – mice lacking these muscarinic acetylcholine receptors were found to
lack REM sleep. Done using CRISPR knockout approach.
28. Niwa Y, Kanda GN, Yamada RG, et al.: Muscarinic Acetylcholine Receptors Chrm1 and Chrm3 Are Essential for REM
Sleep.Cell Rep. 2018; 24(9): 2231–2247.e7.

Ppargc1a, Unc13c – sleep quality QTL identified in a GWA study. Noth involved in
synaptic plasticity and transmission. Honestly I’m not sure I understand much of the
forward genetic mapping section
59. Chen Z, Cooper B, Kalla S, et al.: The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-
dependent recovery at a central synapse.J Neurosci. 2013; 33(119): 8336–51

60. Dougherty SE, Bartley AF, Lucas EK, et al.: Mice lacking the transcriptional coactivator PGC-1α exhibit alterations in
inhibitory synaptic transmission in the motor cortex.Neuroscience. 2014; 271: 137–48.

Ntm, Snx19 –QTLs found to correlate with resumption of activity when mapping
variability in a collaborative cross breeding population. Involved in neural cell adhesion
and insulin-containing vesicles maintenance
70. Philip VM, Sokoloff G, Ackert-Bicknell CL, et al.: Genetic analysis in the Collaborative Cross breeding population.Genome
Res. 2011; 21(8): 1223–38.

Homer1 – candidate QTL gene for the increase in delta power after sleep deprivation.
Found with paneling variants in Genetic reference population.
71. Mackiewicz M, Paigen B, Naidoo N, et al.: Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely
candidate.Physiol Genomics. 2008; 33(1): 91–9.

72. Maret S, Dorsaz S, Gurcel L, et al.: Homer1a is a core brain molecular correlate of sleep loss.Proc Natl Acad Sci U S A. 2007;
104(50): 20090–5.

Rarb – QTL gene found to determine contribution of slow waves to NREM EEG
73. Maret S, Franken P, Dauvilliers Y, et al.: Retinoic acid signaling affects cortical synchrony during sleep.Science. 2005;
310(5745): 111–3.

Acot11 – Found to determine the recovery of NREM sleep after sleep deprivation; is an
enzyme involved in fatty acid regulation in the liver. Unclear methods and citation.
78. Hobson JA: Sleep is of the brain, by the brain and for the brain.Nature. 2005; 437(7063): 1254–6

Dec2 – mutation confers short sleep in humans and mice. Found studying familial
pedigrees
85. He Y, Jones CR, Fujiki N, et al.: The transcriptional repressor DEC2 regulates sleep length in mammals.Science. 2009;
325(5942): 866–70.

Adr1 – mutation found in a family with natural short sleeps. Found to cause decreased
protein stability. When put in mice found to reduce sleep times too.
 88. Shi G, Xing L, Wu D, et al.: A Rare Mutation of β1-Adrenergic Receptor Affects Sleep/Wake Behaviors.Neuron. 2019;
103(6): 1044–1055.e7.

Npsr1 – Missense mutation associated with natural short sleep phenotype in humans.
Mice with this expression slept less and resistant to memory deficits of sleep loss.
89. Xing L, Shi G, Mostovoy Y, et al.: Mutant neuropeptide S receptor reduces sleep duration with preserved memory
consolidation.Sci Transl Med. 2019; 11(514): pii: eaax2014

C. elegans

Dmsr-1 – in a mutagenesis screen in Flp-13 overexpressing worms, this gene was found
for modifying the sleep-promoting effect of Flp-13
22. Yuan J, Zhou J, Raizen DM, et al.: High-throughput, motility-based sorter for microswimmers such as C. elegans.Lab Chip.
2015; 15(13): 2790–8.

23. Iannacone MJ, Beets I, Lopes LE, et al.: The RFamide receptor DMSR-1 regulates stress-induced sleep in C. elegans.Elife.
2017; 6: pii: e19837.

Goa-1, Gpb-2 – genes coupled to Dmsr-1 identified in a mutagenesis screen for genes
regulating developmentally timed sleep.
24. Huang H, Zhu CT, Skuja LL, et al.: Genome-Wide Screen for Genes Involved in Caenorhabditis elegans Developmentally
Timed Sleep.G3 (Bethesda). 2017; 7(9): 2907–17.