title: RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids.
abstract: Sex chromosomes are uniquely subject to chromosome-wide silencing during male meiosis, and silencing persists into post-meiotic spermatids. Against this background, a select set of sex chromosome-linked genes escapes silencing and is activated in post-meiotic spermatids. Here, we identify a novel mechanism that regulates escape gene activation in an environment of chromosome-wide silencing in murine germ cells. We show that RNF8-dependent ubiquitination of histone H2A during meiosis establishes active epigenetic modifications, including dimethylation of H3K4 on the sex chromosomes. RNF8-dependent active epigenetic memory, defined by dimethylation of H3K4, persists throughout meiotic division. Various active epigenetic modifications are subsequently established on the sex chromosomes in post-meiotic spermatids. These RNF8-dependent modifications include trimethylation of H3K4, histone lysine crotonylation (Kcr), and incorporation of the histone variant H2AFZ. RNF8-dependent epigenetic programming regulates escape gene activation from inactive sex chromosomes in post-meiotic spermatids. Kcr accumulates at transcriptional start sites of sex-linked genes activated in an RNF8-dependent manner, and a chromatin conformational change is associated with RNF8-dependent epigenetic programming. Furthermore, we demonstrate that this RNF8-dependent pathway is distinct from that which recognizes DNA double-strand breaks. Our results establish a novel connection between a DNA damage response factor (RNF8) and epigenetic programming, specifically in establishing active epigenetic modifications and gene activation.
authors.affiliation: Division of Reproductive Sciences, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Ho-Su
authors.initials: HS
authors.lastname: Sin
authors.forename: Artem
authors.initials: A
authors.lastname: Barski
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kartashov
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.forename: Junjie
authors.initials: J
authors.lastname: Chen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Andreassen
authors.forename: Satoshi H
authors.initials: SH
authors.lastname: Namekawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D057890:Epigenomics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008540:Meiosis; D009690:Nucleic Acid Conformation; D011479:Protamines / Q000378:metabolism; D012730:Sex Chromosomes / Q000378:metabolism*; D013087:Spermatids / Q000378:metabolism; D013090:Spermatocytes / Q000378:metabolism; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D006657:Histones; D011479:Protamines; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases