Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver |
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Authors: | Holly Whitton Larry N. Singh Marissa A. Patrick Andrew J. Price Fernando G. Osorio Carlos López‐Otín Irina M. Bochkis |
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Affiliation: | 1. Broad Institute of MIT and Harvard, Cambridge, MA, USA;2. Center for Mitochondrial and Epigenomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA;3. Department of Pharmacology, University of Virginia, Charlottesville, VA, USA;4. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain;5. Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain |
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Abstract: | Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis. |
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Keywords: | forkhead factors Foxa2 heterochromatin lipid metabolism liver nuclear lamina |
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