DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

Skvortsova, Ksenia; Masle-Farquhar, Etienne; Luu, Phuc-Loi; Song, Jenny Z.; Qu, Wenjia; Zotenko, Elena; Gould, Cathryn M.; Du, Qiyun; Peters, Timothy J.; Colino‐Sanguino, Yolanda; Pidsley, Ruth; Nair, Shalima S.; Khoury, Amanda; Smith, Grady C.; Miosge, Lisa A.; Reed, Joanne H.; Kench, James G.; Rubin, Mark A.; Horvath, Lisa G.; Bogdanović, Ozren; Lim, Sue Mei; Polo, José M.; Goodnow, Christopher C.; Stirzaker, Clare; Clark, Susan J.

doi:10.1016/j.ccell.2019.01.004

Cited by 67 publications

(53 citation statements)

References 87 publications

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“…Consistent with these findings, we found 5hmC enrichment among introns, enhancers, and regions with transcriptionally active chromatin. Furthermore, we observe a depletion of high 5hmC loci among CpG island regions, while an enrichment at CpG island shore regions, consistent with previous findings [8,24], as well as models suggesting the presence of 5hmC at CpG island shore regions prevents methylation encroachment of promoter CpG islands in cancer [30]. Consistent with prior studies, We also observe significant enrichment of high 5hmC CpGs among CpG island shelf and open sea regions [8,24].…”

Section: Discussionsupporting

confidence: 92%

“…Substantial deviation from DNA methylation patterns in normal breast tissue has been observed in premalignant lesions as well as in advanced disease [36,37]. Although 5hmC tends to be depleted in proliferating cells [27,28], recent studies have suggested 5hmC may be involved in the regulation of cancerrelated phenotypes [30,43,54,55]. To assess the potential contribution of 5hmC to breast carcinogenesis, we utilized available data describing regulatory regions present in variant human mammary epithelial cells (vHMECs), proliferative clones of HMECs that invariably result during cell culture, and share several phenotypes with premalignant breast cancers.…”

Section: Normal Breast Tissue 5hmc Is Enriched Among Genomic Regions mentioning

confidence: 99%

“…Emerging evidence also suggests dysregulation of 5hmC abundance may actively contribute to human cancer 2 [6,26]. Global reduction of 5hmC is observed among cancers of diverse tissues [27,28], including breast cancer, and maintenance of 5hmC protects against characteristic cancerassociated CpG island hypermethylation [29,30]. Accordingly, mechanisms that abrogate TET expression and function, ultimately reducing 5hmC production, appear to be ubiquitous across human cancer [31][32][33][34][35].…”

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confidence: 99%

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Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue

Wilkins

Houseman

et al. 2019

Epigenetics

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Despite recent evidence that 5-hydroxymethylcytosine (5hmC) possesses roles in gene regulation distinct from 5-methylcytosine (5mC), relatively little is known regarding the functions of 5hmC in mammalian tissues. To address this issue, we utilized an approach combining both paired bisulfite (BS) and oxidative bisulfite (oxBS) DNA treatment, to resolve genome-wide patterns of 5hmC and 5mC in normal breast tissue from disease-free women. Although less abundant than 5mC, 5hmC was differentially distributed, and consistently enriched among breast-specific enhancers and transcriptionally active chromatin. In contrast, regulatory regions associated with transcriptional inactivity, such as heterochromatin and repressed Polycomb regions, were relatively depleted of 5hmC. Gene regions containing abundant 5hmC were significantly associated with lactate oxidation, immune cell function, and prolactin signaling pathways. Furthermore, genes containing abundant 5hmC were enriched among those actively transcribed in normal breast tissue. Finally, in independent data sets, normal breast tissue 5hmC was significantly enriched among CpG loci demonstrated to have altered methylation in pre-invasive breast cancer and invasive breast tumors. Primarily, our findings identify genomic loci containing abundant 5hmC in breast tissues and provide a genome-wide map of nucleotide-level 5hmC in normal breast tissue. Additionally, these data suggest 5hmC may participate in gene regulatory programs that are dysregulated during breast-related carcinogenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Normal Breast Tissue 5hmc Is Enriched Among Genomic Regions mentioning

confidence: 99%

mentioning

confidence: 99%

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Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue

Wilkins

Houseman

et al. 2019

Epigenetics

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“…Consistent with this model, in a mouse model of BrafV600E-driven colon cancer, escape from senescence and tumor progression was linked to increased expression of Dnmt3b and methylation and silencing of p16 (Carragher et al, 2010). According to this model, although activated BRAFV600E can increase the selective pressure that favors CIMP, methylation is not directly caused by BRAFV600E but has an inherent tendency to encroach on unmethylated CpG islands during aging (Skvortsova et al, 2019;Ushijima and Suzuki, 2019;Tao et al, 2019). In another model that more directly links oncogenic signaling and CIMP, it has been proposed that BRAFV600E signaling recruits DNMT3B to genes silenced by CIMP via the transcriptional repressor, MAFG, thereby directly promoting CIMP (Fang et al, 2014(Fang et al, , 2016.…”

Section: Introductionsupporting

confidence: 52%

DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

et al. 2020

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Approximately 10% of human colorectal cancer (CRC) are associated with activated BRAFV600E mutation, typically in absence of APC mutation and often associated with a CpG island methylator (CIMP) phenotype. To protect from cancer, normal intestinal epithelial cells respond to oncogenic BRAFV600E by activation of intrinsic p53 and p16-dependent tumor suppressor mechanisms, such as cellular senescence. Conversely, CIMP is thought to contribute to bypass of these tumor suppressor mechanisms, e.g. via epigenetic silencing of tumor suppressor genes, such as p16. It has been repeatedly proposed that DNMT3B is responsible for BRAFV600E-induced CIMP in human CRC. Here we set out to test this by in silico, in vitro, and in vivo approaches. We conclude that although both BRAFV600E and DNMT3B harbor oncogenic potential in vitro and in vivo and show some evidence of cooperation in tumor promotion, they do not frequently cooperate to promote CIMP and human intestinal cancer.

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“…Similarly, promoter hypermethylation of tumor suppressor genes has also been considered a common and driving event in breast malignancies. Loss-of-function mutations in DNA hydroxylases ( TET1 , TET2 and TET3 ) or overexpression of DNA methyltransferases ( DNMT1 , DNMT3A and DNMT3B ) 26,27 , and recently tumor hypoxia 28 have been reported to be associated with aberrant DNA methylation, yet the molecular origin of promoter hypermethylation in breast cancer remains obscure 27,29 .…”

Section: Introductionmentioning

confidence: 99%

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

Kusi

Zand

Lin

et al. 2020

Preprint

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17Metabolic reprogramming in cancer cells not only sustains bioenergetic and biosynthetic needs 18 but also influences transcriptional programs, yet how chromatin regulatory networks are rewired 19 by altered metabolism remains elusive. Here we investigate genome-scale chromatin remodeling 20 in response to 2-hydroxyglutarate (2HG) oncometabolite using single-cell assay for transposase 21 accessible chromatin with sequencing (scATAC-seq). We find that 2HG enantiomers differentially 22 disrupt exquisite control of epigenome integrity by limiting α-ketoglutarate (αKG)-dependent DNA 23 and histone demethylation, while enhanced cell-to-cell variability in the chromatin regulatory 24 landscape is most evident upon exposure to L2HG enantiomer. Despite the highly heterogeneous 25 responses, 2HG largely recapitulates two prominent hallmarks of the breast cancer epigenome, 26 i.e., global loss of 5-hydroxymethylcytosine (5hmC) and promoter hypermethylation, particularly 27 at tumor suppressor genes involved in DNA damage repair and checkpoint control. Single-cell 28 mass cytometry further demonstrates downregulation of BRCA1, MSH2 and MLH1 in 2HG-29 responsive subpopulations, along with acute reversal of chromatin remodeling upon withdrawal. 30 Collectively, this study provides a molecular basis for metabolism-epigenome coupling and 31 identifies metabolic vulnerabilities imposed on the breast cancer epigenome. 33 As a dynamic system, cancer cells continuously adapt to the fluctuating microenvironment by 34 rerouting metabolic fluxes and evolve from early initiation through progression and 35 dissemination 1,2 . Metabolic reprogramming in cancer cells facilitates energy production and 36 macromolecular synthesis to fuel cell proliferation 3,4 . In addition to supporting bioenergetic and 37 biosynthetic needs, altered metabolism involves promiscuous production of non-canonical 38 metabolic intermediates, which have been described as metabolic waste products or metabolite 39 damage 5,6 . Recent studies suggest that these previously uncharacterized metabolites including 40 oncometabolites are linked to 'non-metabolic' signaling mechanisms in cell-type-specific fate 41 decisions 7 . 42 The oncometabolite 2-hydroxyglutarate (2HG) occurs as two enantiomers and 43 accumulates up to millimolar concentrations in a broad range of hematological and solid 44 malignancies 8,9 . Somatic mutations in isocitrate dehydrogenase genes, IDH1 and IDH2, found in 45 glioma and acute myeloid leukemia (AML) result in stereospecific production of the D-enantiomer 46 (D2HG) 10,11 , while breast tumors frequently exhibit elevated levels of 2HG despite the lack of IDH 47 mutations 12,13 . Recent studies indicate that the L-enantiomer (L2HG) can accumulate under 48 acidic 14,15 and hypoxic conditions 16,17 that often coexist in the tumor microenvironment, yet the 49 potential sources and functions of L2HG are less well established. Both enantiomers structurally 50 resemble α-ketoglutarate (αKG), a key intermediate ...

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DNA Hypermethylation Encroachment at CpG Island Borders in Cancer Is Predisposed by H3K4 Monomethylation Patterns

Cited by 67 publications

References 87 publications

Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue

Genome-wide characterization of cytosine-specific 5-hydroxymethylation in normal breast tissue

DNMT3B Oncogenic Activity in Human Intestinal Cancer Is Not Linked to CIMP or BRAFV600E Mutation

Single-cell chromatin profiling reveals demethylation-dependent metabolic vulnerabilities of breast cancer epigenome

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