Chromatin and Transcription Transitions of Mammalian Adult Germline Stem Cells and Spermatogenesis

• Published in: Cell stem cell 2014-08, Vol.15 (2), p.239-253
• Main Authors: Hammoud, Saher Sue, Low, Diana H.P., Yi, Chongil, Carrell, Douglas T., Guccione, Ernesto, Cairns, Bradley R.
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2014.04.006

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. [Display omitted] •Self-renewing (Thy1+) versus differentiating (Kit+) germline stem cells are profiled•Thy1+ to Kit+ comparisons reveal major differences in signaling and transcription•Promoters and enhancers for pluripotency genes are “poised” by chromatin•Gametogenesis involves transcription with DNA methylation at many promoters By comparing high-resolution transcriptome and epigenome profiles of mouse adult spermatogonial stem cells and their progeny, Hammoud et al. provide a comprehensive resource useful for gaining insight into state transitions of self-renewing adult somatic stem cells.