Gallardo, AmadorBelmonte-Reche, EfresMarti-Marimon, MaríaDomingo-Reinés, JoanPeris, GuillermoLópez-Onieva, LourdesFernández-Rengel, IvánXie, JiajunTristán-Ramos, PabloBellora Pereyra, NicolásSánchez-Pozo, AntonioEstévez, Antonio M.Heras, Sara R.Marti-Renom, Marc A.Landeira, David2025-10-142025-10-142025Gallardo A, Belmonte-Reche E, Marti-Marimon M, Domingo-Reinés J, Peris G, López-Onieva L, Fernández-Rengel I, Xie J, Tristán-Ramos P, Bellora N, Sánchez-Pozo A, Estévez AM, Heras SR, Marti-Renom MA, Landeira D. BMAL1-TRIM28 represses transposable elements independently of CLOCK in pluripotent cells. Nat Commun. 2025 Sep 10;16(1):8250. DOI: 10.1038/s41467-025-63778-42041-1723http://hdl.handle.net/10230/71496Circadian oscillations of gene transcripts rely on a negative feedback loop executed by the activating BMAL1-CLOCK heterodimer and its negative regulators PER and CRY. Although circadian rhythms and CLOCK protein are mostly absent during embryogenesis, the lack of BMAL1 during prenatal development causes an early aging phenotype during adulthood, suggesting that BMAL1 performs an unknown non-circadian function during organism development that is fundamental for healthy adult life. Here, we show that BMAL1 interacts with TRIM28 and facilitates H3K9me3-mediated repression of transposable elements in naïve pluripotent cells, and that the loss of BMAL1 function induces a widespread transcriptional activation of MERVL elements, 3D genome reorganization and the acquisition of totipotency-associated molecular and cellular features. We propose that during embryogenesis, BMAL1 is redeployed as a transcriptional repressor of transposons in a CLOCK-independent way, and the activity of BMAL1-TRIM28 during prenatal life might protect mammalian organisms from premature aging during adulthood.application/pdfeng© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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-nc-nd/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-025-63778-4Embryonic stem cellsEpigenomicsTranspositioninfo:eu-repo/semantics/openAccess