Research Article: Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Date Published: February 27, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Holly Whitton, Larry N. Singh, Marissa A. Patrick, Andrew J. Price, Fernando G. Osorio, Carlos López‐Otín, Irina M. Bochkis.


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.

Partial Text

Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope is a common mechanism underlying metabolic disease susceptibility and age‐dependent metabolic changes (Lopez‐Otin, Galluzzi, Freije, Madeo & Kroemer, 2016). A recent report implicated disorganization of heterochromatin at the lamina as a driver of human aging (Zhang et al., 2015). Mutations in LMNA, encoding the nuclear structural protein lamin A/C, result in disturbed nuclear architecture and cause the premature aging syndrome Hutchinson‐Gilford progeria (HGPS). Additionally, LMNA mutations lead to partial lipodystrophy, a condition associated with insulin‐resistant diabetes, hypertriglyceridemia, and hepatic steatosis (Shackleton et al., 2000). Multiple enzymes modulating covalent modifications to lysine 9 of histone 3 (H3K9), the mark associated with heterochromatin in lamina‐associated domains (Guelen et al., 2008), have been linked to fatty liver, hyperlipidemia, diabetes, and obesity (Picard et al., 2002; Sun et al., 2012; Tateishi, Okada, Kallin & Zhang, 2009; Villeneuve et al., 2008; Wang et al., 2013). We have recently implicated lamina‐associated factors Hdac3 and Srf in age‐dependent dysregulation of lipid metabolism in the liver (Bochkis, Przybylski, Chen & Regev, 2014). However, the mechanism relating chromatin disorganization at the nuclear lamina to metabolic defects is unknown.

Here, we used an unbiased approach to investigate changes in LADs in aging and are providing these data sets as a resource to the field. While this work is the first to connect regulation of chromatin at the nuclear lamina to binding of pioneer factors in mammalian aging and age‐dependent metabolic dysfunction, Mango and colleagues have reported that binding of pha‐4, an ortholog of Foxa proteins in Caenorhabditis elegans, is restricted by emerin, a nuclear lamina component, in the pharynx during foregut development. On this basis, they concluded that nuclear lamina interferes with binding of pha‐4, preventing global decompaction and reorganization of chromatin (Fakhouri, Stevenson, Chisholm & Mango, 2010). Collectively, these observations indicate that the relationship between lamina components and pioneer factors is conserved and warrants further investigation.

None declared.

H.W. performed experiments. L.N.S., M.A.P., and A.J.P. analyzed data. F.G.O. and C. L. O. contributed to studies with Zmpste24 mutant mice. I.M.B. developed the project, performed experiments, analyzed data, and wrote the draft of the manuscript.




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