Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells

Mayor, Regina; Muñoz, Mar; Coolen, Marcel W.; Custodio, Joaquín; Esteller, Manel; Clark, Susan J.; Peinado, Miguel A.

doi:10.4161/epi.6.9.16066

Cited by 7 publications

(13 citation statements)

References 47 publications

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“…The regional epigenetic architecture and the regulation of LRES have been well characterized in human cancer cells and also its coordinated response to drug induced reactivation (Frigola et al., 2006; Mayor et al., 2011; Rodriguez et al., 2008). We wondered about the dynamics of epigenetic profiles in these regions under a physiological process.…”

Section: Resultsmentioning

confidence: 99%

“…Bisulfite treatment was performed using the EZ DNA methylation kitTM (Zymo Research). Specific genomic regions were amplified by nested PCR (primers are listed in Supplementary Table 3 and Mayor et al., 2011). Methylation analysis was carried out on pooled PCR products by direct PCR sequencing with the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…RNA and the corresponding cDNA were obtained using standard protocols. Gene expression was quantified using the ABI PRISM 7900 HT sequence detection system (Applied Biosystems) and primers described in references (Frigola et al., 2006; Mayor et al., 2011), or Light Cycler 2.0 real time PCR system (Roche Diagnostics), and primers listed in Supplementary Table 1. The reactions were performed in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…The analysis of the LRES chromatin landscape in cancer cells treated with epigenetic drugs points out that this phenomenon may result from the overtaking of chromatin boundaries determining the autonomous regulation of domains with different functional properties (Mayor et al., 2011; Rodriguez et al., 2008). However, the regulation of these regions in normal cells and the dynamics of the concurrent silencing during tumor progression remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Long range epigenetic silencing is a trans‐species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells

et al. 2013

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DNA methylation and chromatin remodeling are frequently implicated in the silencing of genes involved in carcinogenesis. Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types. However, it is unknown whether there is a coordinated regulation of the genes embedded in these regions in normal cells and in early stages of tumor progression. To better characterize the molecular events associated with the regulation and remodeling of these regions we analyzed two regions undergoing LRES in human colon cancer in the mouse model. We demonstrate that LRES also occurs in murine cancer in vivo and mimics the molecular features of the human phenomenon, namely, downregulation of gene expression, acquisition of inactive histone marks, and DNA hypermethylation of specific CpG islands. The genes embedded in these regions showed a dynamic and autonomous regulation during mouse intestinal cell differentiation, indicating that, in the framework considered here, the coordinated regulation in LRES is restricted to cancer. Unexpectedly, benign adenomas in Apc(Min/+) mice showed overexpression of most of the genes affected by LRES in cancer, which suggests that the repressive remodeling of the region is a late event. Chromatin immunoprecipitation analysis of the transcriptional insulator CTCF in mouse colon cancer cells revealed disrupted chromatin domain boundaries as compared with normal cells. Malignant regression of cancer cells by in vitro differentiation resulted in partial reversion of LRES and gain of CTCF binding. We conclude that genes in LRES regions are plastically regulated in cell differentiation and hyperproliferation, but are constrained to a coordinated repression by abolishing boundaries and the autonomous regulation of chromatin domains in cancer cells.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Long range epigenetic silencing is a trans‐species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells

et al. 2013

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“…Besides the interactions between DNA methylation and H3K9me, which may establish and reinforce a silencing loop, polycomb group proteins can modify the methylation status of histone H3 on lysine 27 and recruit other members of repressor complex, including PRC1, which is able to prevent transcriptional activation. 44 In a recent report by Mayo et al 45 the epigenetic profile of two chromosomal regions undergoing long range epigenetic silencing was investigated in colorectal cancer similar to that observed in the MASPIN gene (which encodes a serine protease inhibitor with tumor-suppressor activity) and the MAGE family (for which promoter hypermethylation is responsible for the restricted expression of the tumor-associated MAGE antigens). 3 Like MASPIN and MAGE, the present study suggests that the HYAL1 gene is clearly upregulated by epigenetic therapy.…”

confidence: 99%

Evidence of epigenetic regulation of the tumor suppressor gene cluster flankingRASSF1in breast cancer cell lines

Prando

Cavalli²,

Rainho³

2011

Epigenetics

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The regulatory function of tandem repeat VNTR2‐1 in hTERT gene involves basic Helix–loop–helix family transcription factors

Zhu

2021

Environ and Mol Mutagen

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Telomerase is a ribonucleoprotein enzyme that synthesizes telomere end sequence. The expression of hTERT gene, encoding the catalytic subunit of human telomerase, is restricted to highly proliferative tissues and is undetectable in most somatic cells. Abnormal activation of hTERT gene is found in 90% of human tumors. Previously, we identified tandem repeat of 42‐bp/unit, VNTR2‐1, in intron 2 of the hTERT gene, as a novel regulatory element important for hTERT transcription in cancer cells. In the current study, we found that multiple 42‐bp repeats of VNTR2‐1 activated luciferase gene in reporter plasmids. Mutation of the predicted cis‐regulatory elements within the 42‐bp repeats, including a E‐box motif, resulted in a partial or complete loss of its enhancer activity. Moreover, MYC family proteins, c‐MYC, MAX, and MNT, regulated hTERT gene transcription through both VNTR2‐1 and E‐boxes at the proximal hTERT promoter. Chromatin segmentation analysis of published ChIP‐sequencing data from K562 cells indicated that VNTR2‐1 was a bivalent enhancer. In telomerase‐expressing human melanoma cell line MelJuSo, deletion of VNTR2‐1 caused the hTERT promoter chromatin status to change from an active state to a repressed state, accompanied by increases of H3K27me3 and H3K9me3 marks. Therefore, we provided additional evidence for VNTR2‐1 as a functional regulatory element that regulated hTERT expression by MYC family transcription factors. These results have improved our knowledge on the functions of repetitive genomic DNAs and the regulatory mechanisms of human telomerase gene.

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Dynamics of bivalent chromatin domains upon drug induced reactivation and resilencing in cancer cells

Cited by 7 publications

References 47 publications

Long range epigenetic silencing is a trans‐species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells

Long range epigenetic silencing is a trans‐species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells

Evidence of epigenetic regulation of the tumor suppressor gene cluster flankingRASSF1in breast cancer cell lines

The regulatory function of tandem repeat VNTR2‐1 in hTERT gene involves basic Helix–loop–helix family transcription factors

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