title: Polycomb binding precedes early-life stress responsive DNA methylation at the Avp enhancer.
abstract: Early-life stress (ELS) in mice causes sustained hypomethylation at the downstream Avp enhancer, subsequent overexpression of hypothalamic Avp and increased stress responsivity. The sequence of events leading to Avp enhancer methylation is presently unknown. Here, we used an embryonic stem cell-derived model of hypothalamic-like differentiation together with in vivo experiments to show that binding of polycomb complexes (PcG) preceded the emergence of ELS-responsive DNA methylation and correlated with gene silencing. At the same time, PcG occupancy associated with the presence of Tet proteins preventing DNA methylation. Early hypothalamic-like differentiation triggered PcG eviction, DNA-methyltransferase recruitment and enhancer methylation. Concurrently, binding of the Methyl-CpG-binding and repressor protein MeCP2 increased at the enhancer although Avp expression during later stages of differentiation and the perinatal period continued to increase. Overall, we provide evidence of a new role of PcG proteins in priming ELS-responsive DNA methylation at the Avp enhancer prior to epigenetic programming consistent with the idea that PcG proteins are part of a flexible silencing system during neuronal development.
authors.affiliation: Max-Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany; Manchester Metropolitan University, Manchester, United Kingdom.
authors.forename: Chris
authors.initials: C
authors.lastname: Murgatroyd
authors.affiliation: Max-Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Spengler
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000235:genetics*; D002454:Cell Differentiation; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011485:Protein Binding; D013312:Stress, Physiological
chemical_list: D002843:Chromatin; D006657:Histones; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D063146:Polycomb-Group Proteins; C494163:Suz12 protein, mouse; D001127:Arginine Vasopressin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D063151:Polycomb Repressive Complex 2