Acetylation reprograms MITF target selectivity and residence time
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ABSTRACT:
PROVIDER: PRJNA573049 | ENA |
REPOSITORIES: ENA
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Project description:Key to effective gene regulation in development and homeostasis is the ability of transcription factors to discriminate between different classes of binding sites. Yet how this is achieved is poorly understood. The microphthalmia-associated transcription factor MITF is a lineage-survival oncogene that plays a crucial role in melanoma and melanocyte development where it suppresses invasion but promotes both proliferation and differentiation. How MITF distinguishes between differentiation and proliferation-associated targets is unknown. Unexpectedly we show here that differentiation-associated target genes are characterized by low affinity MITF binding sites. MAPK signaling, a key driver of melanomagenesis downstream from BRAF and NRAS, promotes p300/CBP-mediated MITF acetylation at K206 to reduce preferentially DNA binding affinity at differentiation-associated targets. The results reveal a MAPK-driven acetylation switch that can trigger de-differentiation of melanocytes and provide a mechanistic explanation of why a human K206Q MITF mutation is associated with Waardenburg’s syndrome characterized by pigmentation abnormalities.
2023-08-07 | GSE137776 | GEO
Project description:Raw files for the manuscript from Yang et al. Reversible lysine-targeted probes reveal residence time-based kinase selectivity
2022-02-26 | MSV000088924 | MassIVE
Project description:MITF reprograms the extracellular matrix and focal adhesion in melanoma
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Project description:To assess the effects of permanent loss of MITF in melanoma cells, we used the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 technique to generate MITF knockout (KO) cell lines in the human hypo-tetraploid SkMel28 melanoma cell line (containing four copies of MITF). We targeted exon 6 (containing the DNA binding domain) of MITF the resulting isogenic cell line is hereafter referred to as ΔMITF-X6. We also performed siRNA mediated transient knock down of MITF along with control siCTRL in 501Mel cells. Furthermore, we used a stable doxycycline inducible over-expression cell line containing FLAG tagged MITF and a control cells with empty vector FLAG in A375P. From our RNA-sequencing studies we found that MITF plays a critical role as a repressor of extracellular matrix gene expression and is actively involved in shaping the microenvironment of melanoma cells in a cell-autonomous manner.
2020-12-22 | GSE163646 | GEO
Project description:MITF is the master regulator of the melanocyte lineage and a melanoma lineage oncogene. It controls a wide range of target genes fulfilling many distinct functions, but relatively little is known about how its DNA-binding is regulated to select the correct target genes. The datasets presented here were used investigate the effects of MAPK signaling-induced MITF-acetylation on MITF activity in melanoma cells through ChIP-Seq of wild-type and acetyl-mutant MITF.
2021-02-12 | GSE77437 | GEO
Project description:Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone acetylation mediated memory
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Project description:Histone modifications, largely regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been recognized as major regulatory mechanisms governing human diseases including cancer. Despite significant effort and recent advances, the mechanism by which the p300 transcriptional coactivator mediates tumorigenesis remains unclear. Here, we use a genetic and chemical approach to identify the Microphthalmia-associated transcription factor (MITF) as a critical downstream target of p300 driving human melanoma growth. We find that direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions is coupled to cellular proliferation, suggesting a significant growth regulatory axis. Further analysis revealed Forkhead Box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell growth, which is selectively activated in human melanomas. Targeted chemical inhibition of p300 histone acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor confirmed the critical role of the p300-MITF-FOXM1 axis in melanoma and demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. These data support p300 as a promising novel epigenetic therapeutic target in human melanoma.
2020-03-22 | GSE128737 | GEO
Project description:Histone deacetylases (HDACs) are critical in the control of gene expression and dysregulation of their activity has been implicated in a broad range of diseases including cancer, cardiovascular and neurological diseases. HDAC inhibitors (HDACi) employing different zinc chelating functionalities such as hydroxamic acids and benzamides have shown promising results in cancer therapy. While it has also been suggested that HDACi with increased isozyme-selectivity and potency may broaden their clinical utility and minimize side effects, the translation of this idea to the clinic remains to be investigated. Moreover, a detailed understanding of how HDACi with different pharmacological properties affect biological functions in vitro and in vivo is still missing. Here we show that a panel of benzamide-containing HDACi are slow tight-binding inhibitors with long residence times unlike the hydroxamate-containing HDACi SAHA and TSA. Characterization of changes in H2BK5 and H4K14 acetylation following HDACi treatment in the neuroblastoma cell line SH-SY5Y revealed that the timing and magnitude of histoneacetylation mirrored both the association and dissociation kinetic rates of the inhibitors. In contrast, cell viability and microarray gene expression analysis indicated that cell death induction and changes in transcriptional regulation do not correlate with the dissociation kinetic rates of the HDACi. Therefore, our study suggests that the evaluation of different classes of HDACi compounds using recombinant HDACs or histone acetylation is insufficient to predict their functional impact on cell activity. Control, SAHA 6hr, SAHA 24hr, SAHA 24hr (pulsed), C1 6hr, C1, 24hr, C1 24hr (pulsed)
2013-08-01 | E-GEOD-49158 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE33149: Substrate selectivity for semisynthetic CK2 proteins with various posttranslational modifications GSE33150: Substrate selectivity for semisynthetic CK2 proteins with Pin1 Refer to individual Series
2011-10-24 | E-GEOD-33151 | biostudies-arrayexpress
Project description:The MITF-low melanoma transcriptional signature is predictive of poor outcome for patients but little is known about its biological signature. We used genetic models of zebrafish with low expression of mitfa (MITF-low) to study this biological subtype. We performed whole bulk RNA-seq to classify zebrafish MITF-low melanoma that cluster mainly by their directionality of growth and assess their resemblance to patients’ MITF-low subgroups. Furthermore, using genetic inhibition of MITF activity we discover minimal residual disease at the site of regression and using single-cell and low input RNA-seq we characterise these MITF independent cells and show that they pre-exist in the primary tumour.
2019-10-09 | GSE130037 | GEO