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Liver gene regulatory networks: Contributing factors to nonalcoholic fatty liver disease

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Abstract Metabolic diseases such as nonalcoholic fatty liver disease (NAFLD) result from complex interactions between intrinsic and extrinsic factors, including genetics and exposure to obesogenic environments. These risk factors converge in aberrant gene expression patterns in the liver, which are underlined by altered cis‐regulatory networks. In homeostasis and in disease states, liver cis‐regulatory networks are established by coordinated action of liver‐enriched transcription factors (TFs), which define enhancer landscapes, activating broad gene programs with spatiotemporal resolution. Recent advances in DNA sequencing have dramatically expanded our ability to map active transcripts, enhancers and TF cistromes, and to define the 3D chromatin topology that contains these elements. Deployment of these technologies has allowed investigation of the molecular processes that regulate liver development and metabolic homeostasis. Moreover, genomic studies of NAFLD patients and NAFLD models have demonstrated that the liver undergoes pervasive regulatory rewiring in NAFLD, which is reflected by aberrant gene expression profiles. We have therefore achieved an unprecedented level of detail in the understanding of liver cis‐regulatory networks, particularly in physiological conditions. Future studies should aim to map active regulatory elements with added levels of resolution, addressing how the chromatin landscapes of different cell lineages contribute to and are altered in NAFLD and NAFLD‐associated metabolic states. Such efforts would provide additional clues into the molecular factors that trigger this disease. This article is categorized under: Biological Mechanisms > Metabolism Biological Mechanisms > Regulatory Biology Laboratory Methods and Technologies > Genetic/Genomic Methods
Liver spatial, epigenomic, and transcriptomic zonation. A gradient of oxygen, nutrients, hormones, and Wnt morphogens underlies the functional spatial zonation of liver cells along the porto‐central axis, in which periportal hepatocytes show higher levels of the master regulator transcription factor HNF4A. Among other processes, HNF4A contributes to the repression of Wnt‐regulated pericentral genes and to the induction of genes that are essential for gluconeogenesis and cholesterol biosynthesis
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Liver metabolic homeostasis is underlined by complex cis‐regulatory networks, which integrate different intrinsic and extrinsic signaling cues via cooperative binding of liver‐enriched transcription factors (TFs) to regulatory elements, such as enhancers and promoters. Such cues include the appropriate establishment of lineage‐commitment gene programs during embryonic development, the dynamic exposure to metabolites and cytokines in the hepatic niche, as well as oscillations of autonomous and nonautonomous circadian TFs. When either one of these processes is altered, a broad rewiring of liver chromatin landscapes occurs, leading to pervasive changes in the transcriptomes of different liver cell types and loss of metabolic homeostasis. Altogether, these processes lead to aberrant metabolic profiles, increasing NAFLD risk and/or accelerating its progression
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Regulation of liver cis‐regulatory networks by fasting and feeding. Different cistromes operate in fasting and fed states in the liver, ensuring maintenance of metabolic homeostasis. Failure to maintain these cistromes, for example by loss of PPARα or BCL6, promotes steatosis
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Genome browser screenshot depicting the human HNF4A locus (hg19 assembly) with epigenomic datasets released by Roadmap Epigenomics and ENCODE. Datasets were compiled using the Roadmap Epigenomics grid visualization function and visualized using the WashU EpiGenome Browser (http://epigenomegateway.wustl.edu/browser/). A comparison of transcriptomic and epigenomic features for human adult liver and the hepatocellular carcinoma cell line HepG2, which is commonly used to define liver epigenomic landscapes is provided. Most features are shared between primary tissue and the cell line, even if with different degrees of enrichment. Nevertheless, it is worth mentioning that a few liver H3K27ac‐enriched regions, located downstream of HNF4A, are not active in HepG2 cells
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Summary of major available human and mouse liver epigenomic datasets.a Numbers in cells denote number of different samples per dataset. Cell color intensities correlate with number of datasets represented, where darker cells represent datasets with more samples
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Biological Mechanisms > Metabolism
Laboratory Methods and Technologies > Genetic/Genomic Methods
Biological Mechanisms > Regulatory Biology

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