De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

Masalmeh, Roza H. Ali; Taglini, Francesca; Rubio-Ramon, Cristina; Musialik, Kamila I.; Higham, Jonathan; Davidson‐Smith, Hazel; Kafetzopoulos, Ioannis; Pawlicka, Kamila; Finan, Hannah; Clark, Richard; Wills, Jimi; Finch, Andrew J.; Murphy, Lee; Sproul, Duncan

doi:10.1038/s41467-020-20716-w

Cited by 36 publications

(38 citation statements)

References 81 publications

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“…5A). This suggests that DNMT3B LOF does not strongly affect the activity of SETD2 histone H3K36 methyltransferase in ICF1 iPSCs and is consistent with the observations that deposition of H3K36me3 by SETD2 is an event upstream of DNMT3B mediated methylation [22,23,35,53].…”

Section: Corrected Dnmt3b Cannot Overcome the Highest Abnormal Increa...supporting

confidence: 89%

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

Krishnan

Morone

Toubiana

et al. 2022

Preprint

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BackgroundBi-allelic hypomorphic mutations in DNMT3B disrupt DNA methyltransferase activity and lead to Immunodeficiency, Centromeric instability, Facial anomalies syndrome, type 1 (ICF1). While several ICF1 phenotypes have been linked to abnormally hypomethylated repetitive regions, the unique genomic regions responsible for the remaining disease phenotypes remain largely uncharacterized. Here we explored two ICF1 patient-induced pluripotent stem cells (iPSCs) and their CRISPR/Cas9 corrected clones to determine whether gene correction can overcome DNA methylation defects and related/associated changes in the epigenome of non-repetitive regions.ResultsHypomethylated regions throughout the genome are highly comparable between ICF1 iPSCs carrying different DNMT3B variants, and significantly overlap with those in ICF1-peripheral blood and lymphoblastoid cell lines. These regions include large CpG island domains, as well as promoters and enhancers of several lineage-specific genes, in particular immune-related, suggesting that they are pre- marked during early development. The gene corrected ICF1 iPSCs reveal that the majority of phenotype- related hypomethylated regions re-acquire normal DNA methylation levels following editing. However, at the most severely hypomethylated regions in ICF1 iPSCs, which also display the highest increased H3K4me3 levels and enrichment of CTCF-binding motifs, the epigenetic memory persisted, and hypomethylation was uncorrected.ConclusionsRestoring the catalytic activity of DNMT3B rescues the majority of the aberrant ICF1 epigenome. However, a small fraction of the genome is resilient to this reversal, highlighting the challenge of reverting disease states that are due to genome-wide epigenetic perturbations. Uncovering the basis for the persistent epigenetic memory will promote the development of strategies to overcome this obstacle.

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Section: Corrected Dnmt3b Cannot Overcome the Highest Abnormal Increa...supporting

confidence: 89%

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

Krishnan

Morone

Toubiana

et al. 2022

Preprint

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“…However, accumulating evidence indicates that epigenetic alterations generated by dysregulation of epigenetic modifiers play pivotal roles in the initiation, promotion, and progression of colon cancer [ 14 , 15 , 16 , 17 ]. Especially, histone modification is increasingly recognized as an essential process to control oncogenic transcription program and influence the occurrence and development of colon cancer [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. The detailed mechanisms to link histone modification to altering gene expression and promoting colonic carcinogenesis, however, remain unclear.…”

Section: Introductionmentioning

confidence: 99%

VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer

et al. 2021

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Histone modification is aberrantly regulated in cancer and generates an unbalanced state of gene transcription. VprBP, a recently identified kinase, phosphorylates histone H2A on threonine 120 (T120) and is involved in oncogenic transcriptional dysregulation; however, its specific role in colon cancer is undefined. Here, we show that VprBP is overexpressed in colon cancer and directly contributes to epigenetic gene silencing and cancer pathogenesis. Mechanistically, the observed function of VprBP is mediated through H2AT120 phosphorylation (H2AT120p)-driven transcriptional repression of growth regulatory genes, resulting in a significantly higher proliferative capacity of colon cancer cells. Our preclinical studies using organoid and xenograft models demonstrate that treatment with the VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating a transcriptional program resembling that of normal cells. Collectively, our work describes VprBP as a master kinase contributing to the development and progression of colon cancer, making it a new molecular target for novel therapeutic strategies.

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“…Hence, promoter CGIs that are qualified as unmethylated in whole-genome bisulfite sequencing experiments could be protected against DNA methylation through a high 5mC oxidation rate. However, chromatin marks found at promoters (i.e., H3K4me3) can repress DNMT activity, providing an additional mechanism that could explain the lack of detectable DNA methylation at CGIs ( 83 , 84 ). Here, by overexpressing either a catalytically active or inactive domain of TET2, we could highlight various operating modes of this protein.…”

Section: Discussionmentioning

confidence: 99%

TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

et al. 2022

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Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression by controlling the chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs, and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. The TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC-binding motifs and down-regulated a panel of known MYC-repressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease–like state that contributes to an exacerbated sensitivity to autophagy inducers.

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De novo DNA methyltransferase activity in colorectal cancer is directed towards H3K36me3 marked CpG islands

Cited by 36 publications

References 81 publications

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

The rescue of epigenomic abnormalities in ICF1 patient iPSCs following DNMT3B correction is incomplete at a residual fraction of H3K4me3-enriched regions

VprBP directs epigenetic gene silencing through histone H2A phosphorylation in colon cancer

TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

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