Saher Sue Hammoud1,4, Diana Low2,3, Chongil Yi1, Douglas T. Carrell4, Ernesto Guccione*2,3 and Bradley R. Cairns*1
1 Howard Hughes Medical Institute, Department of Oncological Sciences, and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112
2 Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics & Differentiation, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673
3 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore Singapore 119074
4 Department of Surgery (Urology), Obstetrics and Gynecology, and Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah, USA
* Corresponding author
Published on line in Cell Stem Cell on 15 May 2014.
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.
Figure Legend: Summary schematic of transcription and chromatin transitions within the germ cell cycle
For more information on Ernesto Guccione’s laboratory, please click here.