Metabolic resilience is encoded in genome plasticity

Leandro Z. Agudelo, Remy Tuyeres, Claudia Llinares, Alvaro Morcuende, Yongjin Park, Na Sun, Suvi Linna-Kuosmanen, Naeimeh Atabaki-Pasdar, Li-Lun Ho, Kyriakitsa Galani, Paul W. Franks, Burak Kutlu, Kevin Grove, Teresa Femenia, Manolis Kellis

Forskningsoutput: Working paper/PreprintPreprint (i preprint-arkiv)


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 how
resource-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 to
nutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fat
tissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1A
condensates. We find evolutionary adaptations in several dimensions; low conservation of amino acid residues within
protein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stability
through cis-regulatory anchoring and encoding of genome plasticity in radial chromatin organization. We show that
environmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization of
lipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidative
stress, 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 structural
relationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptional
organization 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 large
heterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanism
maintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity through
transcriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-like
adaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here a
general principle by which transcription uses environmental fluctuations for genome function, and demonstrate how
resource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesity
as an inhibitor of genome plasticity relevant for many diseases.
Antal sidor26
StatusPublished - 2021

Ämnesklassifikation (UKÄ)

  • Biokemi och molekylärbiologi


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