Aberrant gene expression induced by a high fat diet is linked to H3K9 acetylation in the promoter-proximal region
Introduction
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting ~25% of the global population [1]. NAFLD is associated with obesity, and is a risk factor for other metabolic diseases such as type 2 diabetes and cardiovascular disease [2,3]. The liver is a critical tissue for energy homeostasis, switching its genetic programs to execute anabolic or catabolic functions in response to nutrient availability. The precise regulation of chromatin structure together with transcription factor activity enables the liver to activate or suppress gene networks in response to energy needs.
Nutrients and intermediates of cell metabolism serve as cofactors for chromatin-modifying enzymes to connect metabolic information with transcriptional control of gene expression [4]. The histone code states that DNA transcription is regulated in part by post-translational chemical modifications to histone proteins. Histone tails are extensively modified by ‘writers’, enzymes that utilize cellular metabolites such as acetyl-CoA, S-adenosylmethionine, or ATP as substrates, as well as ‘erasers’, enzymes that remove these modifications. Histone modifications act as recruiters of transcription factors and/or co-regulators to promote euchromatin or heterochromatin, activating or inactivating gene expression.
A key aspect of the pathophysiology of metabolic disease is abnormal transcriptional control of gene expression, and ongoing studies are providing evidence that epigenetic mechanisms contribute to its progression [4,5]. Excess calorie consumption from carbohydrates and fats are main drivers of energy imbalance and alterations in metabolic pathways. Histone acetylation is highly sensitive to the availability of glucose-derived cytosolic acetyl-CoA [[6], [7], [8], [9], [10]]. In addition, several metabolites and cofactors generated through glycolysis, including acetyl-CoA, pyruvate and lactate, directly alter lysine acetyltransferase or deacetylase activity to link energy status with cellular and organismal homeostasis [11,12]. Acetylation of histone 3 at lysine 9 (H3K9ac) is a marker of actively transcribing genes [[13], [14], [15]], and it has been shown to be necessary for recruitment of the Super Elongation Complex to chromatin and transition from RNA Polymerase II (RNAPII) pause-release to transcript elongation [16,17]. We questioned whether high-fat diet feeding elicits genome-wide alterations in H3K9ac, and using high-throughput technologies we explored the connection between this histone modification and gene expression in this mouse model of NAFLD.
Section snippets
Animals
All animal studies were in accordance with the National Institutes of Health guidelines and were approved by the Indiana University School of Medicine Institutional Animal Care and Use Committee. Control mice from the IL6 receptor knockout colony (cre+ wild type or cre−flox/flox) were used for these studies [18]. The colony is maintained in a C57BL/6J background. Eight-week old male mice were fed a control (2018SX, 18% kcal fat, Envigo, a crude laboratory chow diet) or a high-fat diet (D12492,
Glycolysis flux influences global levels of histone acetylation at specific residues
Intermediates of cell metabolism are used as cofactors for histone-modifying enzymes to link metabolic information with transcriptional control of gene programs [4]. To investigate the connection between changes in glycolysis and histone acetylation, we overexpressed the first enzyme in the glycolysis pathway, glucokinase. Previous studies have shown that increasing glycolysis flux through glucokinase overexpression activates the entire glycolysis and lipogenesis program, including l-pyruvate
Discussion
Aberrant transcriptional control of gene expression is central to the pathophysiology of metabolic diseases. Hundreds of genes become dysregulated and their gene products are abnormally expressed, leading to cellular dysfunction. Ongoing studies are providing evidence that epigenetic changes contribute to metabolic disease development, and histone modifications are at the center stage, bringing specific factors to chromatin, modifying chromatin dynamics, and influencing RNAPII activity as well
Author contribution statement
Authors have contributed to the study as follows: NM, conceptualization and design of the study; XC, YW, AC, AL, XCD, NM, acquisition of data; SL, AC, AL, YL, YW, JW, NM, analysis and interpretation of data; NM, drafting the article and intellectual content; all authors, final approval of the version.
CRediT authorship contribution statement
Núria Morral: Conceptualization, Methodology, Data curation, Formal analysis, Visualization, Writing - original draft. Sheng Liu: Formal analysis, Visualization, Validation. Abass M. Conteh: Data curation, Formal analysis, Visualization, Validation. Xiaona Chu: Data curation, Validation. Yue Wang: Data curation, Validation. X. Charlie Dong: Data curation, Validation. Yunlong Liu: Formal analysis, Visualization, Validation. Amelia K. Linnemann: Data curation, Formal analysis, Visualization. Jun
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
We thank the staff of the Center for Medical Genomics at Indiana University School of Medicine for high-throughput sequencing analysis, and Dr. Yongyong Hou for technical help. This work was supported by a Biomedical Research Grant (Indiana University School of Medicine), an Indiana University Collaborative Research Grant, and by the Indiana Clinical and Translational Sciences Institute, funded in part by grant #UL1TR002529 from the National Institutes of Health, National Center for Advancing
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