HLH-30/TFEB is necessary for chromatin reorganization and maintenance of cell quiescence during starvation in C. elegans

Munoz-Barrera, M.; Mata-Cabana, A.; Moreno-Rivero, A.; Piubeli, F. A.; Ren-Barroso, B.; Al-Refaie, N.; Gutierrez, G.; Cabianca, D. S.; Olmedo, M.

doi:10.1101/2025.10.31.685810

bioRxiv · 10.1101/2025.10.31.685810

HLH-30/TFEB is necessary for chromatin reorganization and maintenance of cell quiescence during starvation in C. elegans

Munoz-Barrera, M.·Mata-Cabana, A.·Moreno-Rivero, A.·Piubeli, F. A.·Ren-Barroso, B.·Al-Refaie, N.·Gutierrez, G.·Cabianca, D. S.·Olmedo, M.

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Abstract

Cellular quiescence is a metabolically active, non-proliferative state critical for tissue maintenance and regenerative capacity, with broad implications for aging and age-related diseases. In Caenorhabditis elegans, L1 developmental arrest upon hatching in the absence of food provides a robust in vivo model to study quiescence. Here, we investigate the roles of the transcription factors HLH-30/TFEB and DAF-16/FOXO during L1 arrest. We show that HLH-30 and DAF-16 collaborate to ensure survival under starvation, with reciprocal regulation of their subcellular localization and transcriptional activity. HLH-30 exerts broad transcriptional control during L1 arrest, modulating genes involved in chromosome organization and cell cycle progression. Profiling of chromatin spatial distribution reveals that HLH-30 is required for fasting-induced 3D chromatin reorganization. Loss of HLH-30 disrupts seam cell cycle arrest and leads to overactivation of the pioneer transcription factor BLMP-1, leading to premature initiation of developmental programs under starvation. Our findings uncover previously unrecognized functions of HLH-30 in genome architecture and quiescence regulation, highlighting conserved mechanisms of transcriptional control during nutrient deprivation with implications for aging and disease.

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Munoz-Barrera, M., Mata-Cabana, A., Moreno-Rivero, A., Piubeli, F. A., Ren-Barroso, B., Al-Refaie, N., Gutierrez, G., Cabianca, D. S., Olmedo, M.. 2025-11-03. HLH-30/TFEB is necessary for chromatin reorganization and maintenance of cell quiescence during starvation in C. elegans. https://doi.org/10.1101/2025.10.31.685810

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