Metabolic resilience is encoded in genome plasticity

• Metabolism plays a central role in evolution, as resource conservation is a selective pressure for fitness and survival.Resource-driven adaptations offer a good model to study evolutionary innovation more broadly. It remains unknown howresource-driven optimization of genome function integrates chromatin architecture with transcriptional phase transitions.Here we show that tuning of genome architecture and heterotypic transcriptional condensates mediate resilience tonutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fattissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1Acondensates. We find evolutionary adaptations in several dimensions; low conservation of amino acid residues withinprotein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stabilitythrough cis-regulatory anchoring and encoding of genome plasticity in radial chromatin organization. We show thatenvironmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization oflipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidativestress, and fatty-acid mediated cellular acidification, enabling endurance of condensate chromatin conformations.Comparative genomics of genetic and diet perturbations reveal mammalian convergence of phenotype and structuralrelationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptionalorganization is encoded in functional divergence of metabolic disease variant-hubs, heterotypic condensate composition,and protein residues sensing metabolic variation. During fuel restriction, these features license the formation of largeheterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanismmaintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity throughtranscriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-likeadaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here ageneral principle by which transcription uses environmental fluctuations for genome function, and demonstrate howresource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesityas an inhibitor of genome plasticity relevant for many diseases.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

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