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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Modulation of SAM/SAH ratio by nutrient availability also alters the kinetics of histone methylation marks. Mentch et al. (2015) initially observed that methionine restriction, but not other amino acids, was sufficient to deplete SAM in HCT116 cells. The evaluation of histone trimethylation marks revealed that the H3K4me3 mark was the most responsive to methionine depletion. Restoration of methionine supply led to rapid recovery of SAM and H3K4me3 levels to that of baseline, suggesting highly dynamic regulation of histone methylation by cellular metabolism. H3K4me3 ChIP-seq analysis of methionine replete-or restriction-cultured cells unveiled that H3K4me3 peaks were decreased mainly at the transcription start sites of genes. As H3K4me3 is a signature for active transcription, the loss of H3K4me3 resulted in the decreased expression of genes enriched with H3K4me3 at their TSS region, among which are cancer-associated genes AKT1, MYC, and MAPK. Methionine restriction in vivo also led to depletion of SAM and corresponding changes in histone H3K4me3 and gene transcription. Hence, targeting of one carbon metabolism has the potential to suppress SAM production and reverse epigenetic dysfunction caused by DNA/histone hypermethylation in cancer cells.
Genetic and Epigenetic Considerations in iPSC Technology
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Histone 3 lysine 4 trimethylation (H3K4me3) is associated with gene activation and enriched in active and poised promoter regions. Since the H3K4me3 level in the promoter is strongly correlated with gene expression, H3K4me3 plays an important role in gene activation (74). In somatic cells, H3K4me3 pattern is similar to that in ESCs, but several pluripotent genes do not harbor H3K4me3 in their promoters (75). During iPSC reprogramming, there are two big waves of global H3K4me3 changes (16). The first wave occurs at the early stage of reprogramming and coincides with both gain and loss of H3K4me3, while the second wave includes only gain of H3K4me3 at the late stage. For example, fibroblast growth factor 4, which is highly expressed in ESCs and essential for their lineage commitment (76), is induced by the first wave of H3K4me3 gain. Lin28, which is expressed in mature iPSCs and promotes iPSC reprogramming (77), is activated by the second H3K4me3 gain.
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
The modification of histone tails has also been linked to the carcinogenic properties of BaP. For example, BaP exposure alters genome-wide H3K9 histone acetylation profiles in MCF7 breast cancer cells (Sadikovic et al., 2008). Moreover, Hela cells exposure to BaP facilitates the enrichment of histone H3 trimethylated at lysine 4 (H3K4Me3) and histone H3 acetylated at lysine 9 (H3K9Ac), two chromatin markers of transcriptional activation, while reducing the association between DNMT1 and the L1 promoter. The cellular DNMT1 expression is subsequently reduced via proteasome-dependent degradation, and cytosine methylation within the L1 promoter CpG island decreases (Teneng et al., 2011).