Setd1b, encoding a histone 3 lysine 4 methyltransferase, is a maternal effect gene required for the oogenic gene expression program

Development. 2017 Jul 15;144(14):2606-2617. doi: 10.1242/dev.143347. Epub 2017 Jun 15.

Abstract

Germ cell development involves major reprogramming of the epigenome to prime the zygote for totipotency. Histone 3 lysine 4 (H3K4) methylations are universal epigenetic marks mediated in mammals by six H3K4 methyltransferases related to fly Trithorax, including two yeast Set1 orthologs: Setd1a and Setd1b. Whereas Setd1a plays no role in oogenesis, we report that Setd1b deficiency causes female sterility in mice. Oocyte-specific Gdf9-iCre conditional knockout (Setd1bGdf9 cKO) ovaries develop through all stages; however, follicular loss accumulated with age and unfertilized metaphase II (MII) oocytes exhibited irregularities of the zona pellucida and meiotic spindle. Most Setd1bGdf9 cKO zygotes remained in the pronuclear stage and displayed polyspermy in the perivitelline space. Expression profiling of Setd1bGdf9 cKO MII oocytes revealed (1) that Setd1b promotes the expression of the major oocyte transcription factors including Obox1, 2, 5, 7, Meis2 and Sall4; and (2) twice as many mRNAs were upregulated than downregulated, suggesting that Setd1b also promotes the expression of negative regulators of oocyte development with multiple Zfp-KRAB factors implicated. Together, these findings indicate that Setd1b serves as maternal effect gene through regulation of the oocyte gene expression program.

Keywords: Histone methylation; Mouse; Oogenesis; Pre-implantation development; Transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blastocyst / cytology
  • Blastocyst / metabolism
  • Epigenesis, Genetic
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Growth Differentiation Factor 9 / deficiency
  • Growth Differentiation Factor 9 / genetics
  • Growth Differentiation Factor 9 / metabolism
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Male
  • Maternal Inheritance
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Oocytes / cytology
  • Oocytes / metabolism
  • Oogenesis / genetics*
  • Oogenesis / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Single-Cell Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zona Pellucida / metabolism
  • Zona Pellucida / pathology
  • Zygote / cytology
  • Zygote / metabolism

Substances

  • Gdf9 protein, mouse
  • Growth Differentiation Factor 9
  • RNA, Messenger
  • Transcription Factors
  • Histone-Lysine N-Methyltransferase
  • Nsccn1 protein, mouse