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.
2025-03-26 | GSE288088 | GEO
Project description: Not available
| S-SCDT-10_1038-S44319-025-00446-0 | biostudies-other
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:Recognition of modified histones by “reader” proteins constitutes a key mechanism regulating diverse chromatin-associated processes important for normal and neoplastic development. For instance, bromodomain-containing proteins bind to acetylated histones and regulate chromatin dynamics and gene expression. We recently identified the YEATS domain as a novel acetyllysine-binding module; however, the functional importance of YEATS domain-containing proteins in human cancer remains largely unknown. Here we show that the YEATS2 gene is highly amplified in human non-small cell lung cancer (NSCLC) and is required for cancer cell growth and survival. Biochemical and crystal structural studies show that YEATS2 binds to acetylated histone H3, and the YEATS domain utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout. ChIP-seq analyses in lung cancer cells reveal that the YEATS2-containing ATAC complex colocalizes with H3K27 acetylation (H3K27ac) on the promoters of actively transcribed genes. Depletion of YEATS2 or disruption of the interaction between its YEATS domain and acetylated histones reduces the ATAC complex-dependent promoter H3K9ac levels and deactivates the expression of essential genes, including the ribosomal protein-encoding genes, which are important for cancer cell growth and survival. Taken together, our study identifies YEATS2 as a histone H3K27ac specific reader that regulates a transcriptional program essential for NSCLC tumorigenesis.
2017-10-31 | GSE90781 | GEO
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.
2023-06-17 | PXD043070 | Pride
Project description:The intracellular O-linked N-acetylglucosamine (O-GlcNAc) modification is known to be enriched in the nucleus and in particular on chromatin, but many of its chromatin targets remain to be identified. Herein we demonstrate the O-GlcNAcylation of YEATS Domain Containing 2 (YEATS2), a subunit of the chromatin Ada-two-A-containing (ATAC) complex and a reader of histone H3K27ac. We show that YEATS2 interacts with the O-GlcNAc transferase (OGT) and further pinpoint its major O-GlcNAcylation site to be Thr604 using electron transfer dissociation mass spectrometry. O-GlcNAcylation promotes the chromatin association of YEATS2, and the affinity between YEATS2 and other ATAC components on chromatin, such as ZZZ3, GCN5 and PCAF. Downstream, YEATS2-T604A attenuated the ATAC-dependent histone H3K9ac levels and inactivated the expression of essential ribosomal genes as shown in chromatin immunoprecipitation assays. Further, xenograft experiments show that YEATS2 O-GlcNAcylation promotes lung cancer tumorigenesis. Our work reveals the critical role of YEATS2 O-GlcNAcylation in stabilizing the ATAC complex on chromatin and expands the chromatin substrates of OGT.
2025-07-28 | PXD060970 | Pride
Project description:YEATS2, a chromatin-associated factor, is essential for maintaining dopaminergic (DA) synaptic integrity, but the underlying mechanism remains unclear. Using Drosophila, we show that neuronal depletion of YEATS2 alters brain transcriptomes, downregulating metabolic genes and upregulating G protein–coupled receptors (GPCRs). This correlates with elevated intracellular calcium levels, leading to neurobehavioral deficits and selective DA neuron loss. Crucially, genetic or pharmacological inhibition of the store-operated calcium entry channel Orai restores calcium balance and rescues DA neuron survival. These findings reveal a YEATS2-dependent epigenetic–calcium axis critical for dopaminergic neuron vulnerability.
2026-04-11 | GSE307078 | GEO
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.
2013-12-02 | E-GEOD-52595 | biostudies-arrayexpress
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:Regulation of gene expression is an integral cellular process, fine-tuned by epigenetic marks like histone modifications. Perturbations in the activity or abundance of epigenetic factors can lead, or contribute to tumorigenesis in healthy cells. Remarkably, the addition of epigenetic marks is dependent on the metabolites produced during several essential cellular pathways. Here, we have explored the interplay between a highly expressed epigenetic factor YEATS2, and a metabolic enzyme GCDH in regulating epithelial to mesenchymal transition in head and neck cancer. We report the results of RNA-seq in YEATS2-silenced BICR10 cells to investigate the effect of YEATS2 in influencing gene expression globally. We have also performed ChIP-seq using YEATS2 antibody in BICR10 cells to obtain the globally occupied sites of YEATS2. Lastly, we report the changes in crotonylation at histone 3 lysine 27 (H3K27Cr) upon YEATS2 downregulation in BICR10 by performing ChIP-seq in shControl vs. shYEATS2 cells.
2025-07-15 | GSE275977 | GEO