TY - JOUR
T1 - Chromatin and transcription transitions of mammalian adult germline stem cells and spermatogenesis
AU - Hammoud, Saher Sue
AU - Low, Diana H.P.
AU - Yi, Chongil
AU - Carrell, Douglas T.
AU - Guccione, Ernesto
AU - Cairns, Bradley R.
N1 - Funding Information:
We thank Brian Dalley for sequencing expertise; Ken Boucher for statistical analysis; and David Nix, Tim Mosbruger, Brett Milash, Darren Ames, and Tim Parnell for bioinformatics assistance. We thank Doria Filipponi and Susanna Dolci for germ cell purification protocols, Antonis Giannakakis for ChIP-seq libraries, and Marco Bezzi and Shun Xie Teo for help with mouse husbandry. Financial support was from a JCO-ASTAR grant (JCOAG03_FG06_2009) and IMCB-A ∗ STAR core funding (to E.G. and D.L); the Department of Urology, University of Utah; the Howard Hughes Medical Institute (HHMI) (genomics, biologicals); and CA24014 for Huntsman Cancer Institute core facilities. S.S.H. is funded by the Helen Hay Whitney Foundation. B.R.C. is an investigator with HHMI.
PY - 2014/8/7
Y1 - 2014/8/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84905911865&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2014.04.006
DO - 10.1016/j.stem.2014.04.006
M3 - Article
C2 - 24835570
AN - SCOPUS:84905911865
SN - 1934-5909
VL - 15
SP - 239
EP - 253
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 2
ER -