title: Transcription and imprinting dynamics in developing postnatal male germline stem cells.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA;
authors.forename: Saher Sue
authors.initials: SS
authors.lastname: Hammoud
authors.affiliation: Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore;
authors.forename: Diana H P
authors.initials: DH
authors.lastname: Low
authors.affiliation: Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
authors.forename: Chongil
authors.initials: C
authors.lastname: Yi
authors.affiliation: Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore;
authors.forename: Chee Leng
authors.initials: CL
authors.lastname: Lee
authors.affiliation: Center for Reproductive Biology, School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA;
authors.forename: Jon M
authors.initials: JM
authors.lastname: Oatley
authors.affiliation: Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA; Human Molecular Genetics Program, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois 60614, USA;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Payne
authors.affiliation: Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Carrell
authors.affiliation: Division of Cancer Genetics and Therapeutics, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.affiliation: Howard Hughes Medical Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA; Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA;
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Cairns
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology* / Q000502:physiology*; D000818:Animals; D015820:Cadherins / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation; D057890:Epigenomics; D005718:Gametogenesis / Q000235:genetics; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting / Q000235:genetics*; D008297:Male; D051379:Mice; D018035:Receptors, Odorant / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D018800:Thy-1 Antigens / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D015820:Cadherins; D018035:Receptors, Odorant; D018800:Thy-1 Antigens; D014157:Transcription Factors
keywords: DNA methylation; germline; imprinting; monoallelic; spermatogonia; stem cells