Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

Stern, Josh Lewis; Paucek, Richard D.; Huang, Franklin W.; Ghandi, Mahmoud; Nwumeh, Ronald; Costello, James C.; Cech, Thomas R.

doi:10.1016/j.celrep.2017.12.001

Cited by 74 publications

(152 citation statements)

References 41 publications

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“…Several studies have identified an association between PRC2 activity, H3K27me3 enrichment, and DNA hypermethylation in tumors [28,30,[35][36][37][38][39]. To investigate the increased DNA methylation in our selected target genes (IRX2, NKX6-1, FOXE1, CABYR, and NRG1), we analyzed H3K4me3 and H3K27me3 enrichment in their promoter regions using ChIp.…”

Section: H3k4me3 H3k27me3 and H3k4me0 Enrichments At Selected Targementioning

confidence: 99%

Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia

Scalea

Maresca²,

Catalanotto

et al. 2019

The FEBS Journal

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The ‘instructive model’ of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation. To provide insight into these conflicting findings, we generated DNA methylation profiles for acute myeloid leukemia samples from patients and leukemic cell lines and integrated them with publicly available ChIp‐seq data, containing H3K4me3 and H3K27me3 CpG island occupation in hESC, or hematopoietic stem or progenitor cells (hHSC/MPP). Hypermethylated CpG islands in AML samples displayed H3K27me3 enrichments in hESC and hHSC/MPP; however, ChIp analysis of specific hypermethylated CpG islands revealed a significant reduction in H3K4me3 signal with a concomitant increase in H3K4me0 levels as opposed to a nonsignificant increase in H3K27me3 marks. The integration of AML DNA methylation profiles with the ChIp‐seq data in hESC and hHSC/MPP also led to the identification of Iroquois homeobox 2 (IRX2) as a previously unknown factor promoting differentiation of leukemic cells. Our results indicate that in contrast to the ‘instructive model’, H3K4me3 levels are strongly associated with DNA methylation patterns in AML and have a role in the regulation of critical genes, such as the putative tumor suppressor IRX2.

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Section: H3k4me3 H3k27me3 and H3k4me0 Enrichments At Selected Targementioning

confidence: 99%

Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia

Scalea

Maresca²,

Catalanotto

et al. 2019

The FEBS Journal

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“…Furthermore, cells that are heterozygous for TERT promoter mutations exhibit allele‐specific characteristics. As an example, the mutant promoter exhibits activating H3K4me2/3 chromatin marks and low CpG methylation upstream of the TSS, while the wild type promoter is epigenetically silenced by the H3K27me3 mark and has dense CpG methylation . In urothelial cancer cell lines, TERT has monoallelic expression, with expression occurring only from the mutant allele …”

Section: Introductionmentioning

confidence: 99%

“…As an example, the mutant promoter exhibits activating H3K4me2/3 chromatin marks and low CpG methylation upstream of the TSS, while the wild type promoter is epigenetically silenced by the H3K27me3 mark and has dense CpG methylation. 23 In urothelial cancer cell lines, TERT has monoallelic expression, with expression occurring only from the mutant allele. 24 TERT expression and telomerase activity are present in thyroid cancer but absent in normal thyroid cells.…”

Section: Introductionmentioning

confidence: 99%

Characterization of human telomerase reverse transcriptase promoter methylation and transcription factor binding in differentiated thyroid cancer cell lines

Avin

Wang

Gilpatrick

et al. 2019

Genes Chromosomes & Cancer

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Telomerase reverse transcriptase (TERT) activation plays an important role in cancer development by enabling the immortalization of cells. TERT regulation is multifaceted, and its promoter methylation has been implicated in controlling expression through alteration in transcription factor binding. We have characterized TERT promoter methylation, transcription factor binding, and TERT expression levels in five differentiated thyroid cancer (DTC) cell lines and six normal thyroid tissue samples by targeted bisulfite sequencing, ChIP‐qPCR, and qRT‐PCR. DTC cell lines express varying levels of TERT and exhibit TERT promoter methylation patterns similar to patterns seen in other telomerase positive cancer cell lines. The minimal promoter immediately surrounding the transcription start site is hypomethylated, while further upstream portions show dense methylation. In contrast, the TERT promoter in normal thyroid tissue is largely unmethylated throughout and expresses TERT minimally. Transcription factor binding is also affected by TERT mutation status. The E‐twenty‐six (ETS) factor GABPA exhibits TERT binding in the TERT mutant DTC cells only, and allele‐specific methylation patterns at the minimal promoter were observed as well, which may indicate allele‐specific factor recruitment at the minimal promoter. Furthermore, we identified binding sites for activators MYC and GSC in the hypermethylated upstream region, pointing to its possible importance in TERT regulation. Overall, TERT expression and telomerase activity depend on the interplay of multiple regulatory mechanisms including TERT promoter methylation, mutation status, and recruitment of transcription factors. This work explores of the interplay between these regulatory mechanisms and offers insight into cellular control of active telomerase in human cancer.

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“…We also investigated THOR region where methylation of CpG sites is generally associated with increased TERT expression 16,36 . However, our data show that increased TERT expression in BCC tumors can be primarily attributed to the promoter mutations as shown in adult gliomas 37 .…”

Section: Discussionmentioning

confidence: 99%

“…The mutations within the TERT promoter create de novo binding sites for ETS transcription factors that lead to increased transcription through massive epigenetic histone modification 14,15 . Methylation within TERT hypermethylated oncological region (THOR) also reportedly de-represses the TERT transcription 16 . Besides TERT promoter, other frequent noncoding mutations in BCC include those involving a bidirectional DPH3 promoter 17 .…”

Section: Introductionmentioning

confidence: 99%

Coding and noncoding somatic mutations in basal cell carcinoma

Maturo

Rachakonda

Heidenreich

et al. 2019

Preprint

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Basal cell carcinoma (BCC) represents the most commonly diagnosed human cancer among persons of European ancestry with etiology mainly attributed to sun-exposure. In this study we investigated mutations in coding and flanking regions of the PTCH1 and TP53 genes and noncoding alterations in the TERT and DPH3 promoters in 191 BCC tumors. In addition, we measured CpG methylation within the TERT hypermethylated oncological region (THOR) and transcriptions levels of the reverse transcriptase subunit. We observed mutations in PTCH1 in 59% and TP53 in 31% of the tumors. Noncoding mutations in TERT and DPH3 promoters were detected in 59% and 38% of the tumors, respectively. We observed a statistically significant co-occurrence of mutations at the four investigated loci. While PTCH1 mutations tended to associate with decreased patient age at diagnosis; TP53 mutations were associated with light skin color and increased number of nevi; TERT and DPH3 promoter with history of cutaneous neoplasms in BCC patients. TERT promoter mutations but not THOR methylation associated with an increased expression of the reverse transcriptase subunit.Our study signifies, in addition to the protein altering mutations in the PTCH1 and TP53 genes, the importance of noncoding mutations in BCC, particularly functional alterations in the TERT promoter. Introduction,

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Allele-Specific DNA Methylation and Its Interplay with Repressive Histone Marks at Promoter-Mutant TERT Genes

Cited by 74 publications

References 41 publications

Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia

Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia

Characterization of human telomerase reverse transcriptase promoter methylation and transcription factor binding in differentiated thyroid cancer cell lines

Coding and noncoding somatic mutations in basal cell carcinoma

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