Open AccessSETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling
Author(s) -
Kentaro Mochizuki,
Yukiko Tando,
Tamotsu Sekinaka,
Kei Otsuka,
Yohei Hayashi,
Hisato Kobayashi,
Asuka Kamio,
Yumi Ito-Matsuoka,
Asuka Takehara,
Toru Kono,
Noriko Osumi,
Yasuhisa Matsui
Publication year - 2018
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.164160
Subject(s) - biology , cell fate determination , microbiology and biotechnology , histone , psychological repression , epigenetics , histone h3 , gene knockdown , signal transduction , embryonic stem cell , gene , cell , mesoderm , germ cell , regulation of gene expression , epiblast , genetics , gene expression , transcription factor , gastrulation
In mouse embryos, Primordial germ cells (PGCs) are fate-determined from epiblast cells. Signaling pathways involved in PGC formation have been identified, but their epigenetic mechanisms remain poorly understood. Here, we show that SETDB1 histone methyltransferase is an epigenetic regulator of PGC fate determination. Setdb1 deficient embryos exhibit drastic reduction of nascent PGCs. Dppa2, Otx2 and Utf1 are de-repressed while mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by Setdb1-knockdown (KD) during PGC-like cell (PGCLC) induction. In addition, binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs, and trimethylation of lysine 9 of Histone H3 is reduced by Setdb1-KD at those regions. Furthermore, DPPA2, OTX2 and UTF1 binding is increased in genes encoding BMP4 signaling-related proteins including SMAD1. Finally, over-expression of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs results in the repression of BMP4 signaling-related genes and PGC determinant genes. We propose that the localization of SETDB1 to Dppa2, Otx2 and Utf1, and subsequent repression of their expression, are crucial for PGC determination by ensuring BMP4 signaling.