Loss of the Polycomb Mark from Bivalent Promoters Leads to Activation of Cancer-Promoting Genes in Colorectal Tumors

Hahn, Maria A.; Li, Arthur X.; Wu, Xiwei; Yang, Richard H.; Drew, David A.; Rosenberg, Daniel W.; Pfeifer, Gerd P.

doi:10.1158/0008-5472.can-13-3147

Cited by 45 publications

(49 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During colorectal cancer initiation, gains and losses of the H3K4me3 modification at promoters are associated with differential gene expression (86). The loss of the H3K27me3 modification has also been linked to aberrant activation of oncogenic gene transcription, including MKI67 and CD133 , a proliferation marker and a cancer stem cell marker, respectively (87). Moreover, the loss of both H3K4me3 and H3K27me3 modifications is associated with aberrant gains in promoter methylation in colorectal cancer (87).…”

Section: Cis-regulatory Elements Are Targets Of Genetic and Epigenetimentioning

confidence: 99%

“…The loss of the H3K27me3 modification has also been linked to aberrant activation of oncogenic gene transcription, including MKI67 and CD133 , a proliferation marker and a cancer stem cell marker, respectively (87). Moreover, the loss of both H3K4me3 and H3K27me3 modifications is associated with aberrant gains in promoter methylation in colorectal cancer (87). Apparent gains and losses of the H3K27me3 modification at promoters also discriminates androgen deprivation-resistant versus sensitive prostate cancer cells, suggesting a role for epigenetic alterations at promoters during cancer progression (88).…”

Section: Cis-regulatory Elements Are Targets Of Genetic and Epigenetimentioning

confidence: 99%

See 1 more Smart Citation

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

2016

View full text Add to dashboard Cite

The emergence of whole-genome annotation approaches is paving the way for the comprehensive annotation of the human genome across diverse cell and tissue-types exposed to various environmental conditions. This has already unmasked the positions of thousands of functional cis-regulatory elements integral to transcriptional regulation, such as enhancers, promoters and anchors of chromatin interactions that populate the noncoding genome. Recent studies showed that cis-regulatory elements are commonly the targets of genetic and epigenetic alterations associated with aberrant gene expression in cancer. Here we review these findings to showcase the contribution of the noncoding genome and its alteration in the development and progression of cancer. We also highlight the opportunities to translate the biological characterization of genetic and epigenetic alterations in the noncoding cancer genome into novel approaches to treat or monitor disease.

show abstract

Section: Cis-regulatory Elements Are Targets Of Genetic and Epigenetimentioning

confidence: 99%

Section: Cis-regulatory Elements Are Targets Of Genetic and Epigenetimentioning

confidence: 99%

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

2016

View full text Add to dashboard Cite

show abstract

“…Unexpectedly, the majority of genes controlled by such hypermethylated bivalent promoters simultaneously showed increased expression levels in lymphoma samples. An up-regulation of genes controlled by bivalent promoters was recently shown in colorectal cancers17. However, it was reported that hypermethylation led to the continued repression of genes.…”

mentioning

confidence: 94%

Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer

Bernhart

Kretzmer

Holdt

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.

show abstract

“…Emerging evidence indicates that bivalency poises genes for expression and is likely a key regulatory mechanism in transdifferentiation during lineage commitment as well as in dedifferentiation during onset and progression of cancer ( Fig. 1) (20)(21)(22)(23)(24). We propose that partial recapitulation of the bivalent chromatin landscape of pluripotent cells in some cancer types-termed "oncofetal epigenetic control" in this review-can offer novel avenues for the development of specific and selective diagnostic and therapeutic approaches.…”

mentioning

confidence: 85%

“…Although there is a reduction in the number of bivalent sites in cancer through loss of H3K27me3, DNA at bivalent promoters was observed to be hyper-methylated (20,61,62), whereas in normal cells, those promoters tend to have lower levels of methylation, which is accompanied by increased gene expression (63,64). In the context of cancer, bivalency seems to be crucial for keeping cells in a differentiated state as loss of bivalent control at the developmentally regulated HOX genes plays an important role in both oncogenesis and tumor suppression (22,65).…”

Section: Bivalent Epigenetic Landscapementioning

confidence: 99%

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

Zaidi

Frietze

Gordon

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G 1 phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.KEYWORDS bivalency, cancer, epigenetic control, nuclear structure, oncofetal gene expression E pigenetic control of gene expression plays a pivotal role in physiological responsiveness and is often compromised during onset and progression of cancer. Epigenetic changes are heritable but do not involve changes in DNA sequences. Within a given cell, there are many distinct carriers of epigenetic information that are relayed to progeny upon cell division. Epigenetic mechanisms include methylation of CpG residues, modifications of nucleosomal histone proteins, regulation of gene transcription and protein translation by noncoding RNA molecules, and mitotic retention of transcription factors (1)(2)(3)(4)(5)(6)(7)(8). From an architectural perspective, epigenetic control is engaged at multiple levels of nuclear organization from sequence-specific regulatory elements to chromatin remodeling at the nucleosomal level to large-scale inter-and intrachromosomal interactions (9)(10)(11)(12)(13)(14). These epigenetic mechanisms function in a complex but coordinated manner to orchestrate cellular responses to extracellular signals.The cellular epigenetic landscape is dynamically modified by a number of posttranslational modifications of nucleosomal histones (1,3,15,16). These modifications function in concert-a phenomenon described as the histone code-to establish context-dependent chromatin landscapes that control access of transcription factors to gene regulatory regions (1,3,15,16). This review focuses on the bivalent chromatin landscape defined by addition of three methyl moieties to lysine 4 and lysine 27 residues of histone H3 (referred to as histone 3 lysine 4 me3 [H3K4me3] and H3K27me3 throughout this article). Chromatin bivalency, i.e., the presence of both activating H3K4me3 and repressive H3K27me3 modifications at gene promoters, was first ob- Address correspondence to Gary S. Stein, gary.stein@med.uvm.edu. MINIREVIEW cr...

show abstract

Loss of the Polycomb Mark from Bivalent Promoters Leads to Activation of Cancer-Promoting Genes in Colorectal Tumors

Cited by 45 publications

References 50 publications

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

Emergence of the Noncoding Cancer Genome: A Target of Genetic and Epigenetic Alterations

Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer

Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

Contact Info

Product

Resources

About