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Here, we identify roles for the transcription factor zinc finger and BTB domain-containing protein 16 (ZBTB16; also known as promyelocytic leukemia zinc finger (PLZF)) in juvenile mouse undifferentiated spermatogonia (uSPG) in promoting self-renewal and cell-cycle progression to maintain uSPG and transit-amplifying states. Notably, ZBTB16, Spalt-like transcription factor 4 (SALL4) and SRY-box transcription factor 3 (SOX3) colocalize at over 12,000 promoters regulating uSPG and meiosis. These regions largely share broad histone 3 methylation and acetylation (H3K4me3 and H3K27ac), DNA hypomethylation, RNA polymerase II (RNAPol2) and often CCCTC-binding factor (CTCF). Hi-C analyses show robust three-dimensional physical interactions among these cobound promoters, suggesting the existence of a transcription factor and higher-order active chromatin interaction network within uSPG that poises meiotic promoters for subsequent activation. Conversely, these factors do not notably occupy germline-specific promoters driving spermiogenesis, which instead lack promoter\u2013promoter physical interactions and bear DNA hypermethylation, even when active. Overall, ZBTB16 promotes uSPG cell-cycle progression and colocalizes with SALL4, SOX3, CTCF and RNAPol2 to help establish an extensive and interactive chromatin poising network.<\/jats:p>","DOI":"10.1038\/s41594-025-01509-5","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T05:04:25Z","timestamp":1740978265000},"page":"1213-1226","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["ZBTB16\/PLZF regulates juvenile spermatogonial stem cell development through an extensive transcription factor poising network"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-1570","authenticated-orcid":false,"given":"Chongil","family":"Yi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7403-0902","authenticated-orcid":false,"given":"Yuka","family":"Kitamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9060-2042","authenticated-orcid":false,"given":"So","family":"Maezawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1052-943X","authenticated-orcid":false,"given":"Satoshi H.","family":"Namekawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9864-8811","authenticated-orcid":false,"given":"Bradley R.","family":"Cairns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"1509_CR1","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1101\/gad.261925.115","volume":"29","author":"SS Hammoud","year":"2015","unstructured":"Hammoud, S. 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