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Chromatin and Single-Cell RNA- Seq Profiling Reveal Dynamic Signaling and Metabolic Transitions during Human Spermatogonial Stem Cell Development
Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
Univ Utah, Sch Med, Dept Oncol Sci, Howard Hughes Med Inst, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA..
Univ Oxford, Radcliffe Dept Med, MRC Weatherall Inst Mol Med, Oxford OX3 9DS, England..
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2017 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 21, no 4, 533-546 p.Article in journal (Refereed) Published
Abstract [en]

Human adult spermatogonial stem cells (hSSCs) must balance self-renewal and differentiation. To understand how this is achieved, we profiled DNA methylation and open chromatin (ATAC-seq) in SSEA4(+) hSSCs, analyzed bulk and single-cell RNA transcriptomes (RNA-seq) in SSEA4+ hSSCs and differentiating c-KIT+ spermatogonia, and performed validation studies via immunofluorescence. First, DNA hypomethylation at embryonic developmental genes supports their epigenetic "poising'' in hSSCs for future/embryonic expression, while core pluripotency genes (OCT4 and NANOG) were transcriptionally and epigenetically repressed. Interestingly, open chromatin in hSSCs was strikingly enriched in binding sites for pioneer factors (NFYA/B, DMRT1, and hormone receptors). Remarkably, single-cell RNA-seq clustering analysis identified four cellular/developmental states during hSSC differentiation, involving major transitions in cell-cycle and transcriptional regulators, splicing and signaling factors, and glucose/mitochondria regulators. Overall, our results outline the dynamic chromatin/transcription landscape operating in hSSCs and identify crucial molecular pathways that accompany the transition from quiescence to proliferation and differentiation.

Place, publisher, year, edition, pages
CELL PRESS , 2017. Vol. 21, no 4, 533-546 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-337112DOI: 10.1016/j.stem.2017.09.003ISI: 000412344700015PubMedID: 28985528OAI: oai:DiVA.org:uu-337112DiVA: diva2:1168849
Funder
Knut and Alice Wallenberg Foundation
Available from: 2017-12-21 Created: 2017-12-21 Last updated: 2018-01-13Bibliographically approved

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Lindskog, Cecilia

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Science for Life Laboratory, SciLifeLabDepartment of Immunology, Genetics and Pathology
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