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Pacheco-Bernal, I.* ; Becerril-Pérez, F.* ; Bustamante-Zepeda, M.* ; González-Suárez, M.* ; Olmedo-Suárez, M.A.* ; Hernández-Barrientos, L.R.* ; Alarcón-Del-Carmen, A.* ; Escalante-Covarrubias, Q.* ; Mendoza-Viveros, L.* ; Hernández-Lemus, E.* ; León-Del-Río, A.* ; De La Rosa Velázquez, I.A. ; Orozco-Solis, R.* ; Aguilar-Arnal, L.*

Transitions in chromatin conformation shaped by fatty acids and the circadian clock underlie hepatic transcriptional reorganization in obese mice.

Cell. Mol. Life Sci. 81:309 (2024)

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The circadian clock system coordinates metabolic, physiological, and behavioral functions across a 24-h cycle, crucial for adapting to environmental changes. Disruptions in circadian rhythms contribute to major metabolic pathologies like obesity and Type 2 diabetes. Understanding the regulatory mechanisms governing circadian control is vital for identifying therapeutic targets. It is well characterized that chromatin remodeling and 3D structure at genome regulatory elements contributes to circadian transcriptional cycles; yet the impact of rhythmic chromatin topology in metabolic disease is largely unexplored. In this study, we explore how the spatial configuration of the genome adapts to diet, rewiring circadian transcription and contributing to dysfunctional metabolism. We describe daily fluctuations in chromatin contacts between distal regulatory elements of metabolic control genes in livers from lean and obese mice and identify specific lipid-responsive regions recruiting the clock molecular machinery. Interestingly, under high-fat feeding, a distinct interactome for the clock-controlled gene Dbp strategically promotes the expression of distal metabolic genes including Fgf21. Alongside, new chromatin loops between regulatory elements from genes involved in lipid metabolism control contribute to their transcriptional activation. These enhancers are responsive to lipids through CEBPβ, counteracting the circadian repressor REVERBa. Our findings highlight the intricate coupling of circadian gene expression to a dynamic nuclear environment under high-fat feeding, supporting a temporally regulated program of gene expression and transcriptional adaptation to diet.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Chromatin ; Chromatin Conformation ; Circadian Rhythms ; Enhancers ; Genome Regulatory Elements ; Lipid Metabolism ; Obesity ; Transcription; Growth-factor 21; Gene-expression; Fgf21; Organization; Architecture; Enhancers; Domains; Binding; Bmal1; Liver

ISSN (print) / ISBN 1420-682X

e-ISSN 1420-9071

Journal Cellular and Molecular Life Sciences - CMLS

Quellenangaben Volume: 81, Issue: 1, Article Number: 309

Publisher Birkhäuser

Publishing Place Picassoplatz 4, Basel, 4052, Switzerland

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) CF Genomics (CF-GEN)

Grants DGAPA-UNAM
National Council of Humanities, Science and Technology (CONAHCyT)
Early Career Return Grant from The International Center for Genomic Engineering and Biotechnology (ICGEB)
Human Frontiers Science Program Young Investigators' Grant
CONAHCyT
INMEGEN
DGAPA-PAPIIT
PAPIIT, Universidad Nacional Autonoma de Mexico (UNAM)