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

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

RISING STARS: Liver sinusoidal endothelial transcription factors in metabolic homeostasis and disease

“…Cis-regulatory networks involve the coordinated activity of multiple TFs that bind to promoters and enhancers to activate broad gene programmes. The liver has been extensively studied in the contexts of health and disease, particularly NAFLD, to show that there is impaired hepatic TF activity in liver metabolic disease (reviewed in (Cebola 2020)). However, as mentioned earlier, such studies focused on bulk liver tissue analyses and did not have the granularity needed to capture TF activity in specific liver cell populations, such as LSECs.…”

Epigenetics of Hepatic Insulin Resistance

“…While there have been a number of studies characterising histone marks in human liver, both in primary samples and cell lines ( 89 ), there have been limited numbers of association studies which compare histone marks in disease and healthy states. Popular methods for high-throughput profiling of histone modifications include ChIP-seq (chromatin immunoprecipitation followed by sequencing) and more recent variations such as CUT&RUN ( 90 ) and CUT&Tag ( 91 ), which require smaller amounts of starting material, although these are comparatively more technically challenging than assessing DNA methylation.…”

Gene Expression of Liver Tissue and Primary and Secondary Liver Cancer with a Particular Focus on Hepatocellular Carcinoma: A Mini-review on Basic Biomedical Assessment

“…1 In general, liver disease is caused by a complicated interplay between internal and extrinsic variables, such as genetics and exposure to obesogenic environments. 2 These risk factors converge on abnormal gene expression patterns in the liver that are supported by alterations in regulatory networks. Liver regulatory networks are generated in homeostasis and disease states by the coordinated activity of hepatic-enriched transcription factors, which define enhancer landscapes, thus activating large gene programs with spatiotemporal resolution.…”

“…1 New developments in DNA sequencing have significantly increased our ability to map active transcripts, enhancers, and TF cistromes as well as to describe the three-dimensional chromatin topology that comprises these components. 2 These new technologies help researchers investigate the biological pathways that control the growth of the liver as well as metabolic balance. 2 Furthermore, genomic studies on patients with liver disease may reveal the gene expression pattern, from which abnormal gene expression patterns may emerge.…”

“…2 These new technologies help researchers investigate the biological pathways that control the growth of the liver as well as metabolic balance. 2 Furthermore, genomic studies on patients with liver disease may reveal the gene expression pattern, from which abnormal gene expression patterns may emerge. 2 As a result, this can add an unparalleled amount of knowledge to the study of hepatic cis-regulatory networks, particularly for normal and abnormal conditions.…”