CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer

Kemp, Christopher J.; Moore, James M.; Moser, Russell; Bernard, Brady; Teater, Matt; Smith, Leslie E.; Rabaia, Natalia A.; Gurley, Kay E.; Guinney, Justin; Busch, Stephanie; Shaknovich, Rita; Lobanenkov, Victor; Liggitt, Denny; Shmulevich, Ilya; Melnick, Ari; Filippova, Galina N.

doi:10.1016/j.celrep.2014.04.004

Cited by 171 publications

(221 citation statements)

References 21 publications

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“…Kemp et al 25 observed that hemizygous loss of Ctcf destabilised DNA methylation at epigenetically variable CpGs in normal lung tissue of mice, and divergent CpGs from Ctcf +/− lungs were significantly shifted towards cytosine hypermethylation and showed increased variance in methylation. Furthermore, they found significant hypermethylation in Ctcf +/− samples that extended to ~2 kb regions surrounding divergent CpGs 25. The above findings are consistent with our findings, which showed that patients with a heterozygous CTCF deletion showed a higher methylation level genome-wide.…”

Section: Discussionmentioning

confidence: 99%

CTCFdeletion syndrome: clinical features and epigenetic delineation

et al. 2017

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Section: Discussionmentioning

confidence: 99%

CTCFdeletion syndrome: clinical features and epigenetic delineation

et al. 2017

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“…While Ctcf is a well-known insulator protein in mammals, 45 genome-wide studies have recently demonstrated that 20-25% of Ctcfbound sites are located within proximal promoter regions, 46 and enrichment of E2f binding motifs has been identified among Ctcf-bound regions in multiple cell types. 47,48 Furthermore, the chromatin regulatory function of Ctcf has recently been established as a tumor suppressive mechanism, 49 akin to pRb/E2f. These studies substantiate our discovery, and Figure 5 In NPCs, E2fs bind the TSS of genes that are transcriptionally active in neurogenic tissues.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

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Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

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“…Such tumor-specific regulation of CTCF-binding sites by methylation is known (27). It has even been shown that CTCF itself can regulate DNA methylation patterns and that cancerous or immortalized cells, when compared with normal cells, have a distinct CTCFbinding landscape in the genome (28), highlighting the complexity of methylation-related regulation, especially when addressed in a locus-specific manner.…”

Section: Pace4 Splicing Is Regulated By Intraexonic Dna Methylationmentioning

confidence: 99%

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

et al. 2017

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Inhibition of PACE4, a proprotein convertase that is overexpressed in prostate cancer, has been shown to block cancer progression in an androgen-independent manner. However, the basis for its overexpression and its growth-inhibitory effects are mitigated and uncertain. Here, we report that PACE4 pre-mRNA undergoes DNA methylation-sensitive alternative splicing of its terminal exon 3 0 untranslated region, generating an oncogenic, C-terminally modified isoform (PACE4-altCT). We found this isoform to be strongly expressed in prostate cancer cells, where it displayed an enhanced autoactivating process and a distinct intracellular routing that prevented its extracellular secretion. Together, these events led to a dramatic increase in processing of the progrowth differentiation factor pro-GDF15 as the first PACE4 substrate to be identified in prostate cancer. We detected robust expression of PACE4-altCT in other cancer types, suggesting that an oncogenic switch for this proenzyme may offer a therapeutic target not only in advanced prostate cancer but perhaps also more broadly in human cancer. Cancer Res; 77(24); 6863-79. Ó2017 AACR.

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CTCF Haploinsufficiency Destabilizes DNA Methylation and Predisposes to Cancer

Cited by 171 publications

References 21 publications

CTCFdeletion syndrome: clinical features and epigenetic delineation

CTCFdeletion syndrome: clinical features and epigenetic delineation

Tissue-specific targeting of cell fate regulatory genes by E2f factors

PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer

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