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ECLIP-Seq of endogenous/exogenous MYC in MCF-7 cells.

ABSTRACT: MYC binds to thousands of promoters and exerts an amplification effect on expression of most genes. Meanwhile, MYC drives tumourigenesis through the regulation of a unique set of cancer-specific targets that differ from its targets in normal cells. The discrepancy in MYC-mediated gene regulation in tumours versus normal cells has not been fully elucidated. In this study, we discovered that MYC protein has a broad RNA binding spectrum including promoter-associated RNAs (paRNAs) and enhancer RNAs (eRNAs). MYC RNA binding peaks colocalize with its DNA binding sites, but they are not dependent on its HLHLZ domain or transactivation domain. By integrating multiple dimensional data sets from cancer cells and tumour samples, we show that the MYC-bound paRNAs and eRNAs can shape MYC chromatin interaction to regulate gene transcription. Finally, we identified and characterized a novel MYC-bound eRNA, which we refer to as MERG1, that plays essential roles in the ERα+ breast cancer tumourigenesis. Mechanistically, MERG1 interacts with MYC and enhances MYC binding to the enhancer and promoter of the GREB1 gene. This process specifically amplifies expression of the MYC target gene GREB1 and accelerates tumour progression. Our study demonstrates that MYC interaction with paRNAs and eRNAs contribute to its specific amplification of gene expression in tumourigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200344 | GEO | 2025/04/30

REPOSITORIES: GEO

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Total RNA-Seq in MCF-7 cells stably expressing shCtrl or shEXOSC3 RNA.

Project description:MYC binds to thousands of promoters and exerts an amplification effect on expression of most genes. Meanwhile, MYC drives tumourigenesis through the regulation of a unique set of cancer-specific targets that differ from its targets in normal cells. The discrepancy in MYC-mediated gene regulation in tumours versus normal cells has not been fully elucidated. In this study, we discovered that MYC protein has a broad RNA binding spectrum including promoter-associated RNAs (paRNAs) and enhancer RNAs (eRNAs). MYC RNA binding peaks colocalize with its DNA binding sites, but they are not dependent on its HLHLZ domain or transactivation domain. By integrating multiple dimensional data sets from cancer cells and tumour samples, we show that the MYC-bound paRNAs and eRNAs can shape MYC chromatin interaction to regulate gene transcription. Finally, we identified and characterized a novel MYC-bound eRNA, which we refer to as MERG1, that plays essential roles in the ERα+ breast cancer tumourigenesis. Mechanistically, MERG1 interacts with MYC and enhances MYC binding to the enhancer and promoter of the GREB1 gene. This process specifically amplifies expression of the MYC target gene GREB1 and accelerates tumour progression. Our study demonstrates that MYC interaction with paRNAs and eRNAs contribute to its specific amplification of gene expression in tumourigenesis.

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Project description:MYC has been known to bind to thousands of promoters and exert an amplification effect on expression of most genes. Meanwhile, MYC drives tumorigenesis through the regulation of a unique set of cancer-specific targets that differ from its targets in normal cells. However, the mechanism underlying this discrepancy in MYC’s regulation in tumor and normal cells has not been fully elucidated. In this study, we discovered that MYC protein has a broad RNA binding spectrum including promoter-associated RNAs (paRNAs) and enhancer RNAs (eRNAs). MYC’s RNA binding peaks colocalize with its DNA binding sites, but not dependent on its HLHLZ domain or transcription activation domain. By further integrating multiple dimensional data from cancer cells and tumors samples, we have shown that the MYC-bound paRNAs and eRNAs can shape MYC chromatin interaction to regulate gene transcription. Finally, we have mechanistically characterized a MYC-bound eRNA, MERG1, that plays essential roles in the ERα+ breast cancer tumorigenesis. Mechanistically, MERG1 interacts with MYC and enhances MYC’s binding to the enhancer and promoter of GREB1 gene. This process specifically amplifies the target gene GREB1 expression and accelerates tumor progression. Our study demonstrates that MYC’s interaction with paRNAs and eRNAs contribute to its specific amplification of gene expression in tumorigenesis.

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A MYCN-independent mechanism mediating secretome reprogramming and metastasis in MYCN-amplified neuroblastoma

Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.

2023-10-24 | PXD039410 | Pride

Functional Importance of eRNAs for Estrogen-dependent Gene Transcriptional Activation

Project description:The functional importance of gene enhancers in regulated gene expression is well established. In addition to widespread transcription of long non-coding RNA (ncRNA) transcripts in mammalian cells, bidirectional ncRNAs referred to as eRNAs are present on enhancers. However, it has remained unclear whether these eRNAs are functional, or merely a reflection of enhancer activation. Here, we report that 17 ?-estradiol (E2)-bound estrogen receptor alpha (ER?) on enhancers causes a global increase in eRNA transcription on enhancers adjacent to E2 upregulated coding genes. These induced eRNAs, as functional transcripts, appear to exert important roles for the observed ligand-dependent induction of target coding genes, causing an increased strength of specific enhancer:promoter looping initiated by ER? binding. Cohesin, present on many ER?-regulated enhancers even prior to ligand treatment, apparently contributes to E2-dependent gene activation by stabilizing E2/ER?/eRNA-induced enhancer:promoter looping. Our data indicate that eRNAs are likely to exert important functions in many regulated programs of gene transcription. The ChIP-seqs in this study measure the binding landscape of master transcription regulator of estrogen signaling - ER?, together with common histone marks including H3K27ac and H3K4me1 in MCF7 cells. These data serve as the basis to understand the enhancer map and subsequent analysis of eRNA expression using GRO-seq. The GRO-seq measures the trancription of nascent RNAs in the genome. From MCF7 cells treated with veichle or estrodial, we could identify estrogen-regulated eRNAs and subsequently could study their functions.

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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.

2025-03-26 | GSE288088 | GEO

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