Dynamic interaction of MYC enhancer RNA with YEATS2 protein regulates MYC gene transcription in pancreatic cancer
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ABSTRACT:
PROVIDER: PRJNA1216178 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32136281_1.fastq.gz | Fastqsanger.gz | |||
| SRR32136281_2.fastq.gz | Fastqsanger.gz | |||
| SRR32136282_1.fastq.gz | Fastqsanger.gz | |||
| SRR32136282_2.fastq.gz | Fastqsanger.gz | |||
| SRR32136283_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive form of pancreatic cancer with a very low survival rate and limited treatment options. Aberrant expression of MYC oncogene plays a crucial role in the progression of PDAC. Recent reports have established the significance of enhancer RNAs (eRNAs), originated from active enhancer or super-enhancer regions, in controlling gene transcription. Our study has identified how novel MYC eRNAs regulate MYC gene expression during chronic inflammatory condition in pancreatic cells. The higher amount of MYC eRNA has been observed in chronic pancreatitis and in pancreatic cancer patients as well. We have shown that MYC-490 kb eRNA interacts with YEATS2, a histone reader protein of ATAC-HAT complex and augments the association of YEATS2-containing ATAC complex to MYC promoter/enhancer region and thus increases MYC gene expression. A TNF-α induced Tyrosine dephosphorylation cycle regulates the MYC eRNA binding to YEATS2 protein in cancer cell. Thus, our study has added another layer of MYC gene expression regulation by enhancer-driven transcripts which can be used as a potential therapeutic target for treating pancreatic cancer.
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Project description:The transcription factor MYC is overexpressed in most cancers, where it drives multiple hallmarks of cancer progression. MYC is known to promote oncogenic transcription by binding to active promoters. In addition, MYC has also been shown to invade distal enhancers when expressed at oncogenic levels, but this enhancer binding has been proposed to have low gene-regulatory potential. Here, we demonstrate that MYC enhancer binding directly promotes cancer type-specific gene programs predictive of poor patient prognosis. MYC induces transcription of enhancer RNA through recruitment of RNAPII, rather than regulating RNAPII pause-release as is the case at promoters. This is mediated by MYC-induced H3K9 demethylation by KDM3A and acetylation by GCN5, leading to enhancer-specific BRD4 recruitment through its bromodomains, which facilitates RNAPII recruitment. Thus, we propose that MYC drives prognostic cancer type-specific gene programs by promoting RNAPII recruitment to enhancers through induction of an epigenetic switch.
2023-11-30 | PXD039586 | Pride
Project description:We identify a collection of candidate lncRNAs interacted with c-Myc in pancreatic cancer and show for the first time that an lncRNA among them, which is named as c-Myc-stabilizing and activating RNA (MSAR), promotes pancreatic cancer proliferation and metastasis through c-Myc. MSAR enhances the interaction of c-Myc and SNIP1. These findings shed light on the pro-tumorigenic role of MSAR and might provide a novel therapeutic strategy for indirect targeting c-Myc in PDAC.
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Project description:Enhancers play key roles in gene regulation. However, comprehensive enhancer discovery is challenging because most enhancers, especially those affected in complex diseases, have weak effects on gene expression. Through gene regulatory network modeling, we identified that dynamic cell state transitions, a critical missing component in prevalent enhancer discovery strategies, can be utilized to improve the cells’ sensitivity to enhancer perturbation. Guided by the modeling results, we performed a mid-transition CRISPRi-based enhancer screen utilizing human embryonic stem cell definitive endoderm differentiation as a dynamic transition system. The screen discovered a comprehensive set of enhancers (4 to 9 per locus) for each of the core lineage-specifying transcription factors (TFs), including many enhancers with weak to moderate effects. Integrating the screening results with enhancer activity measurements (ATAC-seq, H3K27ac ChIP-seq) and three-dimensional enhancer-promoter interaction information (CTCF looping, Hi-C), we were able to develop a CTCF loop-constrained Interaction Activity (CIA) model that can better predict functional enhancers compared to models that rely on Hi-C-based enhancer-promoter contact frequency. Together, our dynamic network-guided enhancer screen and the CIA enhancer prediction model provide generalizable strategies for sensitive and more comprehensive enhancer discovery in both normal and pathological cell state transitions.
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Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs Enhancer usually regulates its targets through physical contact/interaction. In order to study chromosome conformation of Myc locus and potential distal enhancer E1-E5 region in murine AML cells, we utilize the high resolution 4C-seq and analysis pipeline to search cis elements that physical interact with Myc and E1-E5 region through setting up two individual viewpoints in these two regions.
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Project description:Analysis of Gene Expression in KO mice lacking the NOTCH1-bound MYC putative enhancer located at +1.43K downstream of the MYC gene. Enrichment of MYC signature genes were analyzed by GSEA. Results show that MYC expression signature is indeed significantly enriched. Conditional Knockout or WT mice were treated with Tamoxifen or Veicle
2014-09-07 | E-GEOD-57988 | biostudies-arrayexpress
Project description:MYC-MIZ1 protein interaction in germinal center.
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Project description:Enhancer Cis Elements Instruct Promoter-Enhancer Interaction, Promoter-Enhancer Insulation and Compartmental Segregation
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Project description:Lymphomagenesis in the presence of deregulated MYC expression requires suppression of MYC-driven apoptosis, often through downregulation of the pro-apoptotic BCL2L11 gene (Bim). Transcription factors (EBNAs) encoded by the lymphoma-associated Epstein-Barr virus (EBV) activate MYC and silence BCL2L11. We show that EBNA2 upregulates MYC by reconfiguring the 3 Mb MYC locus to increase upstream and decrease downstream enhancer-promoter interactions. EBNA2 recruits the SWI/SNF ATPase BRG1 to drive MYC enhancer-promoter interactions. MYC-Immunoglobulin translocation breakpoints in EBV-positive endemic Burkitt lymphoma localise to EBNA2-activated upstream MYC regions. This implicates EBV in the genesis and localisation of breakpoints, since active enhancers are targeted by activation-induced cytidine deaminase. We identify a novel haematopoietic BCL2L11 enhancer hub that is inactivated by EBNA3A and EBNA3C through recruitment of the H3K27 methyltransferase EZH2. Reversal of enhancer inactivation using an EZH2 inhibitor upregulates BCL2L11 and induces apoptosis. EBV therefore drives lymphomagenesis by hijacking long-range enhancer hubs and specific cellular co-factors. A study of MYC enhancer-promoter interactions using 4C on induction of MYC by the Epstein-Barr virus transcription factor EBNA2 in a lymphoblastoid cell line.
2016-08-04 | E-GEOD-82149 | biostudies-arrayexpress
Project description:Long non-coding RNAs (lncRNAs) function in a wide range of processes by diverse mechanisms, though their roles in regulation of oncogenes and/or tumor suppressors remain rather elusive. We performed a global search for lncRNAs affecting MYC activity using a systems biology-based approach with a K supercomputer and the GIMLET algorism based on local distance correlations. Consequently, MYMLR was identified and experimentally shown to maintain MYC transcriptional activity and cell cycle progression despite the low levels of expression. A proteomic search for MYMLR-binding proteins identified PCBP2, while it was also found that MYMLR places a 557-kb upstream enhancer region in the proximity of the MYC promoter in cooperation with PCBP2. These findings implicate a crucial role for MYMLR in regulation of the archetypical oncogene MYC and warrant future studies regarding the involvement of low copy number lncRNAs in regulation of other crucial oncogenes and tumor suppressor genes.
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