BMAL1-TRIM28 represses transposable elements independently of CLOCK in pluripotent cells

Amador Gallardo, Efres Belmonte-Reche, María Marti-Marimon, Joan Domingo-Reinés, Guillermo Peris, Lourdes López-Onieva, Iván Fernández-Rengel, Jiajun Xie, Pablo Tristán-Ramos, Nicolas Bellora, Antonio Sánchez-Pozo, Antonio M. Estévez, Sara R. Heras, Marc A. Marti-Renom and David Landeira ()
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Amador Gallardo: Avenue de la Ilustración 114
Efres Belmonte-Reche: Avenue de la Ilustración 114
María Marti-Marimon: CNAG
Joan Domingo-Reinés: Avenue de la Ilustración 114
Guillermo Peris: Avenue de la Ilustración 114
Lourdes López-Onieva: Avenue de la Ilustración 114
Iván Fernández-Rengel: Avenue de la Ilustración 114
Jiajun Xie: Avenue de la Ilustración 114
Pablo Tristán-Ramos: Avenue de la Ilustración 114
Nicolas Bellora: Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Antonio Sánchez-Pozo: Avenue de la Ilustración 114
Antonio M. Estévez: Avenida del Conocimiento
Sara R. Heras: Avenue de la Ilustración 114
Marc A. Marti-Renom: CNAG
David Landeira: Avenue de la Ilustración 114

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Circadian 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.

Date: 2025
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DOI: 10.1038/s41467-025-63778-4

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