Saher Sue Hammoud1,2,3,4,14, Diana H.P. Low5,14, Chongil Yi1,2,3, Chee Leng Lee5, Jon M. Oatley6, Christopher J. Payne7,8,9, Douglas T. Carrell10,11,12, Ernesto Guccione5,13 and Bradley R. Cairns1,2,3
1 Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
2 Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
3 Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
4 Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
5 Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore;
6 Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
7 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
8 Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA;
9 Human Molecular Genetics Program, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60614, USA;
10 Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
11 Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
12 Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
13 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
14 These authors contributed equally to this work.
Published in Genes Dev. on 1 Nov, 2015 29: 2312-2324
Postnatal spermatogonial stem cells (SSCs) progress through proliferative and developmental stages to populate the testicular niche prior to productive spermatogenesis. To better understand, we conducted extensive genomic profiling at multiple postnatal stages on subpopulations enriched for particular markers (THY1, KIT, OCT4, ID4, or GFRa1). Overall, our profiles suggest three broad populations of spermatogonia in juveniles: (1) epithelial-like spermatogonia (THY1+; high OCT4, ID4, and GFRa1), (2) more abundant mesenchymal-like spermatogonia (THY1+; moderate OCT4 and ID4; high mesenchymal markers), and (3) (in older juveniles) abundant spermatogonia committing to gametogenesis (high KIT+). Epithelial-like spermatogonia displayed the expected imprinting patterns, but, surprisingly, mesenchymal-like spermatogonia lacked imprinting specifically at paternally imprinted loci but fully restored imprinting prior to puberty. Furthermore, mesenchymal-like spermatogonia also displayed developmentally linked DNA demethylation at meiotic genes and also at certain monoallelic neural genes (e.g., protocadherins and olfactory receptors). We also reveal novel candidate receptor–ligand networks involving SSCs and the developing niche. Taken together, neonates/juveniles contain heterogeneous epithelial-like or mesenchymal-like spermatogonial populations, with the latter displaying extensive DNA methylation/chromatin dynamics. We speculate that this plasticity helps SSCs proliferate and migrate within the developing seminiferous tubule, with proper niche interaction and membrane attachment reverting mesenchymal-like spermatogonial subtype cells back to an epithelial-like state with normal imprinting profiles.
Figure legend: Summary schematic depicting changes in DNAme and transcription during germ cell development. (Top panel) Whereas postnatal
SSCs with high OCT4/ID4 (epithelial-like SSCs) display normal imprinting patterns, THY1+-enriched SSCs (mesenchymal-like
SSCs) at P0-P7 display imprinting defects (high DNAme) at paternally expressed imprinted genes and certain monoallelically expressed
genes but resolve to normal/expected patterns before puberty. THY1++-enriched SSCs transcriptomes enrich for particular GO categories
during development, aligned with needed processes and the germ cell-niche codevelopment.
For more information on Ernesto GUCCIONE 's lab, please click here.