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

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

Author information

1
Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
2
Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology, A(∗)STAR (Agency for Science, Technology and Research), Singapore 119074, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore.
3
Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
4
Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
5
Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology, A(∗)STAR (Agency for Science, Technology and Research), Singapore 119074, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore. Electronic address: eguccione@imcb.a-star.edu.sg.
6
Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: brad.cairns@hci.utah.edu.

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.

PMID:
24835570
DOI:
10.1016/j.stem.2014.04.006
[Indexed for MEDLINE]
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