Cell-to-cell variability in Myc dynamics drives transcriptional heterogeneity in cancer cells
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PROVIDER: EGAS00001007091 | EGA |
REPOSITORIES: EGA
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Project description:The MYC oncogene has been studied for decades, yet there is still intense debate over how this transcription factor controls gene expression. Here, we seek to answer these questions with an in vivo readout of discrete events of gene expression in single cells. We engineered an optogenetic variant of MYC (Pi-MYC) and combined this tool with single-molecule RNA and protein imaging techniques to investigate the role of MYC in modulating transcriptional bursting and transcription factor binding dynamics in human cells. We find that the immediate consequence of MYC overexpression is to increase the duration rather than frequency of bursts, a functional role which is different from the majority of human transcription factors. We further propose that the mechanism by which MYC exerts global effects on the active period of genes is by altering the binding dynamics of transcription factors involved in RNA Polymerase II complex assembly and productive elongation.
2021-12-07 | GSE189943 | GEO
Project description:This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with v-myc myelocytomatosis viral oncogene homolog (avian) (MYC)-associated B-cell lymphomas. Lenalidomide may stop the growth of B-cell lymphomas by blocking the growth of new blood vessels necessary for cancer growth and by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving lenalidomide together with combination chemotherapy may be an effective treatment in patients with B-cell lymphoma.
| 2172376 | ecrin-mdr-crc
Project description:We explored how aging impacts transcriptional dynamics using single-cell RNA-sequencing to profile hundreds of CD4+ T cells from young and old mice from two divergent species. In young animals, immunological challenge drives a conserved transcriptomic switch from highly variable to tightly regulated gene expression, characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging significantly perturbed the activation of this core program, and increased expression heterogeneity across the population of cells in both species.
2016-07-21 | E-MTAB-4888 | biostudies-arrayexpress
Project description:MYC family proteins are oncogenic transcription factors that can globally affect the function of RNA Polymerase II (RNAPII). The ability of MYC proteins to promote transcription elongation depends on their ubiquitination, but the underlying mechanism and its biological relevance are unknown. Here we show that MYC and the Polymerase II associated factor, PAF1c, interact directly and their function is mutually dependent, since the specific binding of MYC to active promoters depends on PAF1c and, conversely, PAF1c is required for MYC-dependent pause release. Upon binding, PAF1c is rapidly transferred from MYC onto RNAPII and this transfer is driven by the HUWE1 ubiquitin ligase. Both MYC and HUWE1 globally control histone H2B ubiquitylation, which promotes transcriptional elongation and alters chromatin structure for double-strand break repair. Consistently, MYC suppresses the accumulation of double-strand breaks at promoters in response to topoisomerase II inhibition. While depletion of PAF1c has only minor effects on MYC-dependent gene expression, MYC induces rampant transcription-dependent DNA damage in PAF1c-depleted cells. We propose that the HUWE1-dependent transfer of PAF1c from MYC onto RNAPII is critical for absorbing the topological stress accompanied with deregulated and oncogenic transcription.
2021-02-15 | PXD023242 | Pride
Project description:Multiple myeloma (MM) remains a challenging hematological malignancy demanding innovative therapeutic strategies. Targeting MYC, the notorious yet traditionally undruggable oncogene, presents an appealing avenue. Here, using a genome-scale CRISPR/Cas9 screen, we identify the WNK lysine deficient protein kinase 1 (WNK1) as a regulator of MYC expression in MM cells. Genetic and pharmacological inhibition of WNK1 reduces MYC expression, and further, disrupts the MYC-dependent transcriptional program. Mechanistically, WNK1 inhibition attenuates the activity of the immunoglobulin heavy chain (IgH) enhancer, thus reducing MYC transcription when this locus is translocated near the MYC locus. WNK1 inhibition profoundly impacts MM cell behaviors, leading to growth inhibition, cell cycle arrest, senescence, and apoptosis. Importantly, the WNK inhibitor WNK463 synergizes with various anti-MM compounds, and inhibits MM growth in primary patient samples as well as xenograft mouse models. Collectively, our study uncovers WNK1 as a potential therapeutic target in MM.
2024-04-18 | PXD051532 |
Project description:Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1- and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S phase, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions.
2022-10-27 | PXD036674 | Pride
Project description:Follicular lymphomas and diffuse large B-cell lymphomas have markedly different biological phenotypes and yet all originate from mature, germinal center B-cells. We hypothesized that alterations in DNA methylation patterning might help explain the clinical heterogeneity of these diseases. We report that intra- and inter-individual patient heterogeneity in cytosine methylation is associated with disease severity, and that methylation heterogeneity originates in germinal centers and is amplified during disease progression. Abnormal methylation patterns differ between chromosomal regions and depend on local gene density and the methylation status of neighboring genes. Lymphomagenic transcriptional regulators, such as BCL6, MYC and EZH2, perturb DNA methylation in a target gene-specific manner. Furthermore, aberrant epigenetic states – especially hypomethylation – tend to spread along DNA in a non-specific manner while insulator elements like CTCF inhibit such spreading. Our findings suggest mechanisms through which altered cytosine methylation contributes to the distinct phenotypes of tumors derived from mature B-cells. Identification of MYC target genes in Burkitt lymphomas by ChIP-on-chip. MYC ChIP-on-chip was done in two Burkitt Lymphoma (BL) cell lines (ramos and mutu3) in duplicate. This submission represents the ChIP-chip component of the study.
2012-11-27 | E-GEOD-31110 | biostudies-arrayexpress
Project description:Multiple myeloma (MM) is a malignant plasma cell disorder and frequently characterized by the 16 dysregulation of the MYC oncogene, which is associated with poor prognosis and disease progression. While MYC's involvement in transcriptional regulation is well-established, the functional role of MYC target proteins and the impact on post-transcriptional processes in MM cells remain poorly understood. This study employed Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) coupled with mass spectrometry analysis to investigate the effects of MYC depletion on the proteome of MM cells. The results revealed that MYC primarily regulates translational processes. Specifically, the three RNA-binding proteins (RBPs) 4EBP1, hnRNPC, and LARP1, were prominently down-regulated upon MYC depletion in MM cells. Notably, high expression levels of these proteins were correlated with poor survival and disease progression in MM patients. These findings highlight the critical role of MYC in the regulation of translation and identify 4EBP1, hnRNPC, and LARP1 as MYC target proteins. Targeting these proteins may offer new therapeutic strategies and prognostic markers for MM, potentially improving patient outcomes. This study provides valuable insights into the post-transcriptional regulatory mechanisms mediated by MYC and opens avenues for further research in understanding and treating this devastating disease.
2023-06-15 | MSV000092169 | MassIVE
Project description:Over-expression of the Myc transcription factor causes its widespread interaction with regulatory domains in the genome, but leads to the up- and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following Myc activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing and mathematical modeling. Transcriptional activation correlated with the highest increases in Myc binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in Myc binding. Altogether, the relative abundance (henceforth, “share”) of Myc at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over Myc’s association with the co-repressor Miz1. Myc activation elicited immediate loading of RNAPII at activated promoters, followed by increases in pause-release5, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the Myc share, suggesting that repression by Myc may be largely indirect, owing - at least in part - to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at Myc regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how over-expressed Myc alters the various phases of the RNAPII cycle and the resulting transcriptional response.
2017-08-23 | GSE98420 | GEO
Project description:Background: Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity, but is difficult to detect and assess functionally. Results: We develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high vs. low cells prospectively isolated GATA1 and GATA2 high vs. low cells. GATA high vs. low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity. Conclusion: Single-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution.
2016-12-12 | GSE76224 | GEO