MAD2L2 Promotes Open Chromatin in Embryonic Stem Cells and Derepresses the Dppa3 Locus.
The chromatin of naive embryonic stem cells (ESCs) has a largely open configuration, as evident by the lack of condensed heterochromatin and the hypomethylation of DNA. Several molecular mechanisms promoting this constellation were previously identified. Here we present evidence for an important epigenetic function of MAD2L2, a protein originally known for its role in DNA damage repair, and for its requirement in germ cell development. We demonstrate using super-resolution microscopy that numerous MAD2L2 microfoci are exclusively associated with euchromatin, similar to other factors of the DNA damage response. In the absence of MAD2L2 the amount of heterochromatin demarcated by H3K9me2 was significantly increased. Among the most strongly suppressed genes was Dppa3, an ESC- and germ-cell-specific gene regulating DNA methylation. In Mad2l2-deficient ESCs 5-methylcytosine levels were globally increased, while several imprinted genes became hypomethylated and transcriptionally activated. Our results emphasize the important function of MAD2L2 for the open chromatin configuration of ESCs.
RG Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, 37077 Göttingen, Germany; DNA Repair and Maintenance of Genome Stability, Max-Delbruck Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
Ali
A
Rahjouei
RG Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, 37077 Göttingen, Germany.
Mehdi
M
Pirouz
DNA Repair and Maintenance of Genome Stability, Max-Delbruck Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
Michela
M
Di Virgilio
Department NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, Am Fassberg, 37077 Göttingen, Germany.
Dirk
D
Kamin
RG Developmental Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg, 37077 Göttingen, Germany. Electronic address: mkessel1@gwdg.de.
Michael
M
Kessel
D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D004249:DNA Damage; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D022041:Euchromatin / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D056426:Genetic Loci; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism; D064246:Mad2 Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015533:Transcriptional Activation
D002868:Chromosomal Proteins, Non-Histone; C462180:Dppa3 protein, mouse; D022041:Euchromatin; D006570:Heterochromatin; D064246:Mad2 Proteins; C577699:Mad2l2 protein, mouse; D012097:Repressor Proteins
DNA damage; DNA methylation; epigenetics; germ cells; heterochromatin