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. 2018 Jun 15;6:e5062.
doi: 10.7717/peerj.5062. eCollection 2018.

Transcriptional Regulation of Metabolism in Disease: From Transcription Factors to Epigenetics

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Free PMC article

Transcriptional Regulation of Metabolism in Disease: From Transcription Factors to Epigenetics

Liam J Hawkins et al. PeerJ. .
Free PMC article

Abstract

Every cell in an individual has largely the same genomic sequence and yet cells in different tissues can present widely different phenotypes. This variation arises because each cell expresses a specific subset of genomic instructions. Control over which instructions, or genes, are expressed is largely controlled by transcriptional regulatory pathways. Each cell must assimilate a huge amount of environmental input, and thus it is of no surprise that transcription is regulated by many intertwining mechanisms. This large regulatory landscape means there are ample possibilities for problems to arise, which in a medical context means the development of disease states. Metabolism within the cell, and more broadly, affects and is affected by transcriptional regulation. Metabolism can therefore contribute to improper transcriptional programming, or pathogenic metabolism can be the result of transcriptional dysregulation. Here, we discuss the established and emerging mechanisms for controling transcription and how they affect metabolism in the context of pathogenesis. Cis- and trans-regulatory elements, microRNA and epigenetic mechanisms such as DNA and histone methylation, all have input into what genes are transcribed. Each has also been implicated in diseases such as metabolic syndrome, various forms of diabetes, and cancer. In this review, we discuss the current understanding of these areas and highlight some natural models that may inspire future therapeutics.

Keywords: Cancer; Diabetes; Epigenetics; Metabolic syndrome; Metabolism; Transcription factors; Transcriptional control.

Conflict of interest statement

Kenneth B. Storey is an Academic Editor for PeerJ.

Figures

Figure 1
Figure 1. General representation of transcriptional regulatory elements.
In eukaryotic transcription, the DNA is present in a three-dimensional orientation where physical interaction between proteins occupying elements of the distal regulatory region and the promoters is possible. Study site: LCRs, locus control regions.
Figure 2
Figure 2. Intrinsic and environmental signals integrate through the epigenome to produce distinct phenotypes from identical genomic information.
Standard cellular, biochemical, physiological, and developmental signals integrate with environmental factors such as diet, toxin exposure, stress, social interactions and developmental conditions through the epigenome to produce numerous phenotypes.
Figure 3
Figure 3. Research into the connections between epigenetics and disease has greatly increased from 1990–2015.
(A) Yearly number of publications on PubMed matching combinatorial search results of “epigenetics” keywords alone, or paired with “disease” keywords. The following search queries were used for “epigenetics”: (epigenetic OR epigenetics OR epigenome OR “histone modification” OR “DNA methylation” OR “histone methylation” OR “histone acetylation”), and “epigenetics and disease”: (epigenetic OR epigenetics OR epigenome OR “histone modification” OR “DNA methylation” OR “histone methylation” OR “histone acetylation”) AND (disease OR disorder OR cancer OR syndrome). (B) Yearly percentage of epigenetics articles (from A) that involve disease.

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Grant support

This work was supported by a Discovery grant (Grant # 6793) from the Natural Sciences and Engineering Research Council (NSERC) of Canada. Kenneth B. Storey holds the Canada Research Chair in Molecular Physiology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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