Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors - PubMed (original) (raw)

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Epigenomic regulation of bile acid metabolism: emerging role of transcriptional cofactors

Zachary Smith et al. Mol Cell Endocrinol. 2013.

Abstract

The traditional role of bile acids is to simply facilitate absorption and digestion of lipid nutrients, but bile acids also act as endocrine signaling molecules that activate nuclear and membrane receptors to control integrative metabolism and energy balance. The mechanisms by which bile acid signals are integrated to regulate target genes are, however, largely unknown. Recently emerging evidence has shown that transcriptional cofactors sense metabolic changes and modulate gene transcription by mediating reversible epigenomic post-translational modifications (PTMs) of histones and chromatin remodeling. Importantly, targeting these epigenomic changes has been a successful approach for treating human diseases, especially cancer. Here, we review emerging roles of transcriptional cofactors in the epigenomic regulation of liver metabolism, especially focusing on bile acid metabolism. Targeting PTMs of histones and chromatin remodelers, together with the bile acid-activated receptors, may provide new therapeutic options for bile acid-related disease, such as cholestasis, obesity, diabetes, and entero-hepatic cancers.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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Figures

Fig.1

Fig.1. Bile acid signaling pathways are complex in the liver

Bile acids are synthesized in the liver from cholesterol by a series of enzymatic reactions, including the first and rate-limiting step catalyzed by Cyp7a1. Bile acids are secreted from the liver into the common bile duct by bile acid transporters, such as, BSEP, and MRP2/3/4, and together with cholesterol, phospholipids, and bilirubin, constitute bile that is stored in the gall bladder. In response to a meal, bile acids are released into the ileum and facilitate digestion of lipid-soluble nutrients. Almost all (95%) of the bile acids are returned to the liver through enterohepatic recycling. Returned bile acids activate FXR, which results in regulation of FXR target genes including the induction of SHP. Bile acids also bind to a membrane receptor, a GPCR protein, TGR5, and probably other unidentified GPCR(s). In the ileum, bile acid-activated FXR induces expression of the intestinal peptide hormone, FGF15, (FGF19 in humans). Then, FGF15 is transported to the liver via the hepatic portal vein and binds its membrane receptor complex, FGFR4 and the coreceptor βKlotho. Binding of bile acids and FGF15 to their membrane receptors triggers cellular kinase signaling cascades to regulate expression bile acid-responsive target genes in hepatocytes.

Fig.2

Fig.2. Epigenetic regulation by chromatin modifying cofactors

The chromatin modifying cofactors, HATs, HDACs, HMTs, HDMs, and chromatin remodelers, such as, ATP-dependent Swi/Snf chromatin remodeling complexes, add or remove gene activation (ex: acetylation of H3K9/K14 and methylation of H3K4) or repression (ex: methylation of H3K9 and H3K27) histone PTMs and mediate chromatin remodeling. These events modulate accessibility of transcriptional machinery to DNA via altered chromatin structure, resulting in gene activation or repression.

Fig.3

Fig.3. SHP functions as a coordinator of epigenetic regulation of Cyp7a1

In response to bile acid signaling, SHP mediates recruitment of chromatin modifying epigenomic cofactors, the HDAC1/2-containing mSin3A corepressor complex, G9a histone lysine methyltransferase, and the Brm-containing Swi/Snf chromatin remodeling complex to the Cyp7a1 promoter, resulting in sequential chromatin modification and gene repression. The recruited HDAC1/2 removes the gene activation histone mark, acetylation at H3K9/K14, G9a adds a gene repression histone mark, methylation at H3K9/K14, and the recruited Brm-containing Swi/Snf mediates chromatin remodeling at the promoter resulting in suppression of Cyp7a1 expression.

Fig.4

Fig.4. Functional specificity of Brm- and Brg-1-containing Swi/Snf complexes in the FXR/SHP-mediated feedback inhibition of hepatic bile acid biosynthesis

A) Mammalian Swi/Snf complexes are ATP-dependent chromatin remodelers comprised of a central ATPase, either Brm or Brg-1, and Brm- or Brg-1-associated factor (BAF) subunits. B) In response to bile acid signaling, the interaction between Brg-1 and FXR is increased, and occupancy of the Brg-1-containing Swi/Snf complex and FXR at the SHP promoter is increased, which results in chromatin remodeling and subsequent gene activation. FXR-induced SHP then interacts with LRH-1 at the Cyp7a1 promoter and inhibits transcription of Cyp7a1 by recruiting chromatin modifying cofactors, including the Brm-containing Swi/Snf complex and other chromatin modifying cofactors like HDACs and G9a, resulting in chromatin remodeling and subsequent gene repression of Cyp7a1. Interestingly, FXR-induced SHP also inhibits transcription of its own gene in a delayed negative auto-regulatory manner. Accessibility of the Shp promoter chromatin to endonuclease is initially increased after bile acid treatment, but, later is decreased, which correlates with the delayed recruitment of SHP and Brm-containing Swi/Snf and other chromatin cofactors to the Shp promoter.

Fig.5

Fig.5. Role of MLL3/4 histone lysine methyltransferases of the ASCOM complexes in the regulation of bile acid homeostasis

A) MLL3 and MLL4 methyltransferases within the ASCOM complexes function as transcriptional coactivators of bile acid-activated FXR. MLL3/4 and ASC-2, a key component of ASCOM complex as the nuclear receptor-interacting cofactor, are recruited to FXR target genes, including Shp, Bsep, Mrp2, and Ntcp, in response to elevated bile acid levels in hepatocytes and mediate methylation at H3K4 and gene activation. B) The MLL3/4-p53-Shp regulatory axis lowers bile acid levels under both normal and stress conditions. The well-known tumor suppressor p53 up-regulates Shp, a key inhibitor of hepatic bile acid biosynthesis, by direct binding to a p53 binding site upstream of the FXR binding site (FXRE) at the Shp promoter. The MLL3/4 methyltransferase of the ASCOM complex is recruited to p53 by a molecular adaptor, p53 binding protein 1 (p53BP1), and coactivates p53 transactivation through methylation at H3K4 at the Shp promoter. C) Under cholestatic conditions, occupancy of MLL3/4 and ASC-2 at the promoters of bile acid transporter genes, including Bsep, Mrp2, and Ntcp, is decreased. Consequently, methylated H3K4 levels are reduced and transcription of hepatic bile acid transporter genes is decreased.

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