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. 2018 Oct 23:9:493.
doi: 10.3389/fgene.2018.00493. eCollection 2018.

IDH1: Linking Metabolism and Epigenetics

Silvia Raineri  1   2 , Jane Mellor  1   2
Affiliations

IDH1: Linking Metabolism and Epigenetics

Silvia Raineri et al. Front Genet. .

Abstract

Mutations in genes encoding enzymes of the tricarboxylic acid cycle often contribute to cancer development and progression by disrupting cell metabolism and altering the epigenetic landscape. This is exemplified by the isoforms of isocitrate dehydrogenase (IDH1/2), which metabolize isocitrate to α-Ketoglutarate (α-KG). Gain of function mutations in IDH1 or IDH2 result in reduced levels of α-KG as a result of increased formation of D-2-Hydroxyglutarate (2-HG). α-KG is an essential co-factor for certain histone and DNA demethylases, while 2-HG is a competitive inhibitor. These IDH1/2 mutations are thought to result in hypermethylated histones and DNA which in turn alters gene expression and drives cancer progression VSports手机版. While this model seems to be generally accepted in the field, the exact molecular mechanisms still remain elusive. How much of this model has been rigorously demonstrated and what is just being assumed. Are the effects genome-wide or focused on specific loci. This Perspective aims at elucidating the key questions that remain to be addressed, the experimental techniques that could be used to gain further insight into the molecular mechanisms involved and the additional consequences of these mutations beyond DNA and protein methylation. .

Keywords: 2HG; IDH1 mutation; TADs; epigenetics; glioma; hypermethylation; metabolism. V体育安卓版.

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Figures

FIGURE 1
FIGURE 1
Current model of the impact of IDH1 mutation on chromatin remodeling. In a WT cell, IDH1/2 (blue and black) metabolize Isocitrate into α-Ketoglutarate. Upon mutation of IDH1 (pink panel), α-Ketoglutarate is processed into 2HG. In other cancer settings, mutations in fumarate hydratase and succinate dehydrogenase result in the accumulation of fumarate and succinate, which may inhibit TETs. α-Ketoglutarate acts as co-factor in the nucleus for both DNA demethylases (TETs) and histone demethylases (KDMs). Their activity ensures the correct levels of DNA (bottom panel) and protein methylation in the cell. More specifically, TETs act on methylated DNA sequences (filled lollipops), starting a reaction chain that will ultimately lead to methyl group removal (empty lollipops).
FIGURE 2
FIGURE 2
Changes in insulation of TADs as a consequence of IDH1 mutation. According to the model suggested by Flavahan et al. (2016, top panel) in a WT IDH1 setting, CTCF is able to bind to particular target sites along the genome, in certain contexts acting as a functional insulator, creating DNA domains that separate neighboring regions. At CTCF binding sites containing the CG dinucleotide, changes in levels of DNA methylation influence its DNA binding. Specifically, the production of 2HG inhibits TETs, leading to hypermethylation (red, filled lollipops) of CTCF-binding sites, reducing binding (right panel). In the context of PDGFRA, the formation of domains sequesters an enhancer upstream the FIP1L1 gene into a separate domain (upper left panel). Upon IDH1 mutation, however, the overall increase in methylation levels due production of 2HG induces loss of CTCF binding to its target sites, leading to loss of insulation between TADs. In this example, destruction of a boundary induces a rearrangement that brings PDGFRA in proximity of an enhancer found upstream the FIP1L1 gene, thus inducing its deregulation (upper right panel). The example described in Modrek et al. (2017) (lower panel) focuses on the SOX2 locus. Here, in the WT IDH1 context, CTCF binding induces the formation of a loop that brings the SOX2 gene and its promoter in close proximity to a downstream enhancer that would be otherwise out of reach (lower left panel). This interaction favors SOX2 expression. Upon a three-hit mechanism that includes mutation of IDH1 and loss of both p53 and ATRX, reduced binding of CTCF at the SOX2 locus impairs the formation of the loop, thus causing a change, rather than a loss, of insulation. In this new setting, the downstream enhancer is too far away to interact with the gene, whose expression is now downregulated (lower right panel). Filled lollipops = methylated DNA; empty lollipops = unmethylated DNA.
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