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Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers [HiChIP]

ABSTRACT: The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112000 | GEO | 2018/03/20

REPOSITORIES: GEO

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Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers [4C-seq]

Project description:The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers.

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Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers [ChIP-seq]

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CTCF-dependent enhancer hijacking by the EVI1 oncogene in leukemia

Project description:Chromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements which are often therapy resistant. In a cohort of primary t(3;8)(q26;q24) AML samples we observed the translocation of a MYC super-enhancer to EVI1. We generated a patient-based t(3;8)(q26;q24) model in vitro using CRISPR-Cas9 technology and demonstrated hyper-activation of EVI1 by the hijacked MYC super-enhancer. One MYC super-enhancer element in particular, which recruits early hematopoietic regulators, is critical for EVI1 expression and enhancer-promoter interaction. This interaction is facilitated by a CTCF-bound motif upstream of the EVI1 promoter that acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of 3q26-rearranged AML samples point to a common mechanism by which EVI1 uses this CTCF-bound enhancer-docking site to hijack early hematopoietic enhancers.

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Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells [RNA-seq]

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Facultative CTCF sites moderate mammary super-enhancer activity and regulate juxtaposed gene in non-mammary cells [4C-seq]

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Chromatin interactions involving super-enhancers associate with specific expression patterns of target genes

Project description:Super-enhancers may regulate target genes through chromatin looping. We connected super-enhancers in the K562 chronic myelogenous leukemia cell line with chromatin interactions identified from Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) data. Gene expression at proximal elements that are connected with distal super-enhancers showed significantly higher cell-type specificity than at proximal elements connected with other elements or not involved in interaction. 4C and Episwitch analysis of chromatin interactions showed that certain chromatin interactions are cell-specific, but others are more general. While super-enhancers upstream of c-MYC at the MYC-335 element can be found in other cancers, only super-enhancers downstream of c-MYC can be found in K562. 4C analysis of the c-MYC promoter revealed no chromatin interactions that are directed upstream of c-MYC, but only downstream of c-MYC, in the PVT1 long non-coding RNA gene. Cell-specific usage of super-enhancers could explain why the MYC-335 element that is associated with many solid cancers such as colorectal cancer and breast cancer, but not with leukemia. Surprisingly, we found that a chromatin interaction between c-MYC and a c-MYC super-enhancer is lost in chronic myelogenous leukemia patient blood as compared with blood from individuals without the disease through Oxford Biodynamicsâ?? Episwitch analysis. These results provide evidence for fine-tuning of expression patterns, such as cell-specific regulation of target genes by distal super-enhancers through chromatin interactions and an association between chromatin interactions and disease, and highlight that super-enhancers are more complex than previously described. Examination of several chromatin interactions involving super-enhancers using 4C-Seq and Episwitch (TM)

2017-05-01 | E-GEOD-77125 | biostudies-arrayexpress

The WNT-dependent gating of MYC requires non-canonical functions of a distal CTCF binding site

Project description:Abnormal WNT signaling increases MYC expression in colon cancer cells in part via oncogenic super-enhancer (OSE)-mediated gating of MYC to the nuclear pore. This process enables MYC transcripts to escape the higher degradation rate in the nucleus compared to the cytoplasm. By targeted mutation, we show here that a single OSE-specific CTCF binding site (CTCFBS) mediates the WNT-regulated increased nuclear export rate of mRNAs derived from its interacting MYC and FAM49B loci, located >0.5 and >2.6 mbp distal of the OSE. The CTCFBS coordinated OSE-MYC proximity with their peripheral localisation, and mediated the WNT-dependent recruitment of the nuclear pore anchor AHCTF1 to the OSE. Furthermore, the CTCFBS up-regulated CCAT1 eRNA transcription, implicated in OSE-MYC interactions, correlating with an enhanced ability of the OSE to reach the nuclear periphery. We submit that WNT-dependent gating of MYC requires CTCF complexed with the OSE to coordinate multiple steps of the gating process.

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Project description:The zinc finger protein CTCF has been invoked in establishing functional boundaries between genes and thereby controlling enhancer activities. However, there is limited genetic evidence to support such a concept. We have now addressed this question in a locus containing five mammary-specific genes controlled by enhancers. We have identified four CTCF binding sites in the casein locus, two at the outside boundaries and two associated with a super-enhancer. Individual deletions of these sites from the mouse genome did not alter expression of the five casein genes and Odam. However, deletion of the border CTCF site separating the Csn1s1 enhancer from non-mammary genes resulted in the activation of Sult1d1 at a distance of more than 95 kb but not the more proximal Sult1e1 gene. Loss of this CTCF site led to de novo interactions between the Csn1s1 enhancer and the Sult1d1 promoter but not with the silent Sult1e1 gene. Our study suggests that most CTCF sites associated with cell-specific enhancers and super-enhancers have no measurable in vivo activity. Only the loss of one CTCF site led to the induction of a juxtaposed active non-target promoter. Our study also demonstrated that cell-specific enhancers are unable to activate juxtaposed silent non-target promoters.

2017-03-24 | GSE92591 | GEO

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2021-07-26 | E-MTAB-9937 | biostudies-arrayexpress

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