Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis.
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.
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.
Saher Sue
SS
Hammoud
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.
Diana H P
DH
Low
Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Chongil
C
Yi
Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Douglas T
DT
Carrell
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.
Ernesto
E
Guccione
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.
Bradley R
BR
Cairns
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism / Q000502:physiology*; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology; D004742:Enhancer Elements, Genetic; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D023281:Genomics; D006657:Histones / Q000737:chemistry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D013091:Spermatogenesis / Q000502:physiology*; D013094:Spermatozoa / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones