Circadian behavior is light-reprogrammed by plastic DNA methylation

The timing of daily circadian behavior can be highly variable among different individuals, and twin studies have suggested that about half of this variability is environmentally controlled. Similar plasticity can be seen in mice exposed to an altered lighting environment, for example, 22-h instead of 24-h, which stably alters the genetically determined period of circadian behavior for months. The mechanisms mediating these environmental influences are unknown. We found that transient exposure of mice to such lighting stably altered global transcription in the suprachiasmatic nucleus (SCN) of the hypothalamus (the master clock tissue regulating circadian behavior in mammals). In parallel, genome-wide methylation profiling revealed global alterations in promoter DNA methylation in the SCN that correlated with these changes. Behavioral, transcriptional and DNA methylation changes were reversible after prolonged re-entrainment to 24-h d. Notably, infusion of a methyltransferase inhibitor to the SCN suppressed period changes. We conclude that the SCN utilizes DNA methylation as a mechanism to drive circadian clock plasticity.

[1]  Wei Li,et al.  Model-based analysis of two-color arrays (MA2C) , 2007, Genome Biology.

[2]  U. Vogel,et al.  Epigenetic Impact of Long-Term Shiftwork: Pilot Evidence From Circadian Genes and Whole-Genome Methylation Analysis , 2011, Chronobiology international.

[3]  Li-Huei Tsai,et al.  Tet1 Is Critical for Neuronal Activity-Regulated Gene Expression and Memory Extinction , 2013, Neuron.

[4]  M. Dahlgren,et al.  Circadian entrainment aftereffects in suprachiasmatic nuclei and peripheral tissues in vitro , 2008, Brain Research.

[5]  Madeleine P. Ball,et al.  Corrigendum: Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells , 2009, Nature Biotechnology.

[6]  Steven A. Brown,et al.  Distinct Roles of DBHS Family Members in the Circadian Transcriptional Feedback Loop , 2012, Molecular and Cellular Biology.

[7]  J. Sweatt,et al.  Cortical DNA methylation maintains remote memory , 2010, Nature Neuroscience.

[8]  F. Milagro,et al.  CLOCK, PER2 and BMAL1 DNA Methylation: Association with Obesity and Metabolic Syndrome Characteristics and Monounsaturated Fat Intake , 2012, Chronobiology international.

[9]  Y. Hur.  Stability of genetic influence on morningness–eveningness: a cross‐sectional examination of South Korean twins from preadolescence to young adulthood , 2007, Journal of sleep research.

[10]  Paolo Sassone-Corsi,et al.  The circadian clock: a framework linking metabolism, epigenetics and neuronal function , 2012, Nature Reviews Neuroscience.

[11]  Sunggu Yang,et al.  Aberrant light directly impairs mood and learning through melanopsin-expressing neurons , 2012, Nature.

[12]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[13]  U. Vogel,et al.  Aberrant DNA methylation of miR‐219 promoter in long‐term night shiftworkers , 2013, Environmental and molecular mutagenesis.

[14]  Steven A. Brown,et al.  Rhythms of Mammalian Body Temperature Can Sustain Peripheral Circadian Clocks , 2002, Current Biology.

[15]  J. David Sweatt,et al.  Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus* , 2006, Journal of Biological Chemistry.

[16]  Steven A. Brown,et al.  Molecular insights into human daily behavior , 2008, Proceedings of the National Academy of Sciences.

[17]  Jennifer J. Loros,et al.  CHD1 Remodels Chromatin and Influences Transient DNA Methylation at the Clock Gene frequency , 2011, PLoS genetics.

[18]  John C. Axley,et al.  Perinatal photoperiod imprints the circadian clock , 2010, Nature Neuroscience.

[19]  J. Kaprio,et al.  Heritability of diurnal type: a nationwide study of 8753 adult twin pairs , 2007, Journal of sleep research.

[20]  W. Johnson,et al.  DNA Demethylase Activity Maintains Intestinal Cells in an Undifferentiated State Following Loss of APC , 2010, Cell.

[21]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[22]  A. Jeltsch,et al.  Mechanistic Insights on the Inhibition of C5 DNA Methyltransferases by Zebularine , 2010, PloS one.

[23]  Thomas Wallach,et al.  A large-scale functional RNAi screen reveals a role for CK2 in the mammalian circadian clock. , 2009, Genes & development.

[24]  P. Pramstaller,et al.  A marker for the end of adolescence , 2004, Current Biology.

[25]  L. Lu,et al.  Tissue-specific modification of clock methylation in aging mice. , 2013, European review for medical and pharmacological sciences.

[26]  W. Huber,et al.  Differential expression analysis for sequence count data , 2010 .

[27]  Daniel J Buysse,et al.  DIURNAL PREFERENCE AND SLEEP QUALITY: SAME GENES? A STUDY OF YOUNG ADULT TWINS , 2010, Chronobiology international.

[28]  W. Lam,et al.  Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells , 2005, Nature Genetics.

[29]  C. Weitz,et al.  Regulation of Daily Locomotor Activity and Sleep by Hypothalamic EGF Receptor Signaling , 2001, Science.

[30]  S. Shimba,et al.  Diurnal expression of Dnmt3b mRNA in mouse liver is regulated by feeding and hepatic clockwork , 2012, Epigenetics.

[31]  Jason P. DeBruyne,et al.  CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock , 2007, Nature Neuroscience.

[32]  Steven A. Brown,et al.  The Period Length of Fibroblast Circadian Gene Expression Varies Widely among Human Individuals , 2005, PLoS biology.

[33]  J. Sweatt,et al.  Epigenetic regulation of memory formation and maintenance. , 2013, Learning & memory.

[34]  Madeleine P. Ball,et al.  Neuronal activity modifies DNA methylation landscape in the adult brain , 2011, Nature Neuroscience.

[35]  J. Sweatt,et al.  Covalent Modification of DNA Regulates Memory Formation , 2007, Neuron.

[36]  Florian Halbritter,et al.  GeneProf: analysis of high-throughput sequencing experiments , 2011, Nature Methods.

[37]  Serge Daan,et al.  A functional analysis of circadian pacemakers in nocturnal rodents , 1976, Journal of comparative physiology.

[38]  Svend K. Petersen-Mahrt,et al.  5-Methylcytosine DNA demethylation: more than losing a methyl group. , 2012, Annual review of genetics.

[39]  F. Holsboer,et al.  Dynamic DNA methylation programs persistent adverse effects of early-life stress , 2009, Nature Neuroscience.

[40]  U. Schibler,et al.  The mammalian circadian timing system: organization and coordination of central and peripheral clocks. , 2010, Annual review of physiology.

[41]  B. Prendergast,et al.  Reversible DNA methylation regulates seasonal photoperiodic time measurement , 2013, Proceedings of the National Academy of Sciences.

[42]  J. Sweatt,et al.  DNA methylation and memory formation , 2010, Nature Neuroscience.

[43]  Satchidananda Panda,et al.  Circadian oscillations of protein-coding and regulatory RNAs in a highly dynamic mammalian liver epigenome. , 2012, Cell metabolism.

[44]  M. Bernstein,et al.  Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2′-deoxycytidine , 2009, Cancer Chemotherapy and Pharmacology.

[45]  J. David Sweatt,et al.  TET1 Controls CNS 5-Methylcytosine Hydroxylation, Active DNA Demethylation, Gene Transcription, and Memory Formation , 2013, Neuron.

[46]  F. Scheer,et al.  The human circadian system adapts to prior photic history , 2011, The Journal of physiology.

[47]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[48]  C. Oakes,et al.  Evaluation of a Quantitative DNA Methylation Analysis Technique using Methylation-Sensitive/Dependent Restriction Enzymes and Real-Time PCR , 2006, Epigenetics.

[49]  Steven A. Brown,et al.  Serum factors in older individuals change cellular clock properties , 2011, Proceedings of the National Academy of Sciences.