Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis

Cell Stem Cell. 2014 Aug 7;15(2):239-53. doi: 10.1016/j.stem.2014.04.006. Epub 2014 May 15.

Abstract

Adult germline stem cells (AGSCs) self-renew (Thy1(+) enriched) or commit to gametogenesis (Kit(+) enriched). To better understand how chromatin regulates AGSC biology and gametogenesis, we derived stage-specific high-resolution profiles of DNA methylation, 5hmC, histone modifications/variants, and RNA-seq in AGSCs and during spermatogenesis. First, we define striking signaling and transcriptional differences between AGSC types, involving key self-renewal and proliferation pathways. Second, key pluripotency factors (e.g., Nanog) are silent in AGSCs and bear particular chromatin/DNAme attributes that may "poise" them for reactivation after fertilization. Third, AGSCs display chromatin "poising/bivalency" of enhancers and promoters for embryonic transcription factors. Remarkably, gametogenesis occurs without significant changes in DNAme and instead involves transcription of DNA-methylated promoters bearing high RNAPol2, H3K9ac, H3K4me3, low CG content, and (often) 5hmC. Furthermore, key findings were confirmed in human sperm. Here, we reveal AGSC signaling asymmetries and chromatin/DNAme strategies in AGSCs to poise key transcription factors and to activate DNA-methylated promoters during gametogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology*
  • Adult Stem Cells / metabolism
  • Animals
  • Cell Differentiation
  • Cell Separation
  • Chromatin / metabolism
  • Chromatin / physiology*
  • DNA Methylation
  • Embryonic Stem Cells / cytology
  • Enhancer Elements, Genetic
  • Flow Cytometry
  • Gene Expression Profiling
  • Genomics
  • Histones / chemistry
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Signal Transduction
  • Spermatogenesis / physiology*
  • Spermatozoa / metabolism
  • Time Factors
  • Transcription, Genetic

Substances

  • Chromatin
  • Histones