Aguirre, SamuelPappa, StellaSerna Pujol, NúriaPadilla, NatàliaIacobucci, SimonaNacht, A. SilvinaVicent, Guillermo PabloJordan Vallès, AlbertCruz, Xavier de laMartínez Balbás, Marian A.2024-09-122024-09-122024Aguirre S, Pappa S, Serna-Pujol N, Padilla N, Iacobucci S, Nacht AS, et al. PHF2-mediated H3K9me balance orchestrates heterochromatin stability and neural progenitor proliferation. EMBO Rep. 2024 Aug;25(8):3486-505. DOI: 10.1038/s44319-024-00178-71469-221Xhttp://hdl.handle.net/10230/61061Heterochromatin stability is crucial for progenitor proliferation during early neurogenesis. It relays on the maintenance of local hubs of H3K9me. However, understanding the formation of efficient localized levels of H3K9me remains limited. To address this question, we used neural stem cells to analyze the function of the H3K9me2 demethylase PHF2, which is crucial for progenitor proliferation. Through mass-spectroscopy and genome-wide assays, we show that PHF2 interacts with heterochromatin components and is enriched at pericentromeric heterochromatin (PcH) boundaries where it maintains transcriptional activity. This binding is essential for silencing the satellite repeats, preventing DNA damage and genome instability. PHF2's depletion increases the transcription of heterochromatic repeats, accompanied by a decrease in H3K9me3 levels and alterations in PcH organization. We further show that PHF2's PHD and catalytic domains are crucial for maintaining PcH stability, thereby safeguarding genome integrity. These results highlight the multifaceted nature of PHF2's functions in maintaining heterochromatin stability and regulating gene expression during neural development. Our study unravels the intricate relationship between heterochromatin stability and progenitor proliferation during mammalian neurogenesis.application/pdfeng© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Commons Public Domain Dedication waiver http://creativecommons.org/publicdomain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s44319-024-00178-7DNA damageHeterochromatin integrityHistone demethylationNeural stem cellsPHF2info:eu-repo/semantics/openAccess