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BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (ChIP-seq)

ABSTRACT: Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61965 | GEO | 2015/04/02

SECONDARY ACCESSION(S): PRJNA262823

REPOSITORIES: GEO

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BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (ChIP-seq)

Project description:Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin. 8 samples corresponding to genomic occupancy profiling of MITF, SOX10, BRG1 after si-control, BRG1 after si-MITF and BRG1 after siSOX10; and their respective controls (MITF Input, SOX10 Input, GFP-siCTRL ChIPseq) in 501Mel cells.

2015-04-02 | E-GEOD-61965 | biostudies-arrayexpress

BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (RNA-seq)

Project description:Microphthalmia-associated transcription factor (MITF) is the master regulator of the melanocyte lineage. By tandem affinity purification and mass spectrometry, we present a comprehensive characterisation of the MITF interactome comprising multiple novel cofactors involved in transcription, DNA replication and repair and chromatin organisation, including a BRG1 chromatin remodelling complex comprising CHD7. BRG1 is essential for melanoma cell proliferation in vitro and for normal melanocyte development in vivo. MITF and SOX10 actively recruit BRG1 to a set of MITF-associated regulatory elements (MAREs) at active enhancers. MITF, SOX10 and YY1 bind between two BRG1-occupied nucleosomes thus defining both a combinatorial signature of transcription factors essential for the melanocyte lineage and a specific chromatin organisation of MAREs. Nevertheless, BRG1 silencing enhances MITF occupancy at MAREs showing that BRG1 acts to promote dynamic MITF interactions with chromatin. 19 samples corresponding to mRNA profiles of 501Mel and Hermes3A after MITF, BRG1 or control shRNA-mediated knockdown were generated by deep sequencing in triplicate (in duplicate for 501_shMITF and corresponding control 501_shSCR2), using HiSeq2500.

2015-04-02 | E-GEOD-61966 | biostudies-arrayexpress

BRG1 recruitment by transcription factors MITF and SOX10 defines a specific configuration of regulatory elements in the melanocyte lineage (RNA-seq)

2015-04-02 | GSE61966 | GEO

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [ChIP-seq]

Project description:Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving development of human melanoma. Mice genetically engineered to conditionally express oncogenic BrafV600E and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks indicating epigenetic reprogramming during tumour progression. Nevertheless, late stage tumour cells grown in culture re-expressed Mitf and melanocyte markers and Mitf together with Sox10 co-regulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brg1 (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brg1 and Bptf co-regulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells

2019-04-17 | GSE100998 | GEO

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [RNA-seq]

Project description:We have used a mouse model where melanoma can be induced by Tamoxifen treatment that induces expression of oncogenic Braf and deletion of Pten in the melanocyte lineage using a Tyr::Cre-ER-T2 transgene to mediate recombination. Cells from these melanoma tumours were cultured in vitro and the effects of siRNA mediated silencing of transcription factors Mitf and Sox10 was performed and analysed by RNA-seq. We then crossed these mice with mice bearing floxed alleles of the genes encoding the chromatin remodelling factors Bptf and Brg1 (Smarca4). Tumour cells were grown in culture and Bptf or Brg1 inactivated by 4-OHT treatment. The effects on gene expression were assessed by RNA-seq.

2019-04-17 | GSE129620 | GEO

Expression data from human metastatic melanoma cell lines

Project description:The genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, that included expression of mRNAs regulated by either transforming growth factor, beta 1 (TGFB1) pathways or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extend this knowledge to include gene expression analyses of 5 additional human melanoma lines, and show that these lines also fall into either TGFB1 or MITF/SOX10 gene expression groups. These mRNA expression studies were followed up by miRNA expression analyses. Microarray analyses were performed on 5 metastatic melanoma lines in 3 replicates. Standard Affymetrix protocols were used.

2014-06-10 | E-GEOD-56717 | biostudies-arrayexpress

DNA Promoter Hypermethylation of Melanocyte Lineage Genes Determines Melanoma Phenotype

Project description:Cellular stress contributes to the capacity of melanoma cells to undergo phenotype switching into highly migratory and drug tolerant dedifferentiated states. Such dedifferentiated melanoma cell states are marked by loss of melanocyte specific gene expression and increase of mesenchymal markers. Two crucial transcription factors, MITF and SOX10, important in melanoma development and progression have been implicated in this process. In this study we describe that loss of MITF is associated with a distinct transcriptional program, MITF promoter hypermethylation and poor patient survival in metastatic melanoma. From a comprehensive collection of melanoma cell lines, we observed that MITF methylated cultures were subdivided in two distinct subtypes. Examining mRNA levels of neural crest associated genes we found that one subtype had lost the expression of several lineage genes including SOX10. Intriguingly, SOX10 loss was associated with SOX10 gene promoter hypermethylation and distinct phenotypic and metastatic properties. Depletion of SOX10 in MITF methylated melanoma cells using CRISPR/Cas9 confirmed these findings. In conclusion, this study describes the significance of melanoma state and the underlying functional properties explaining the aggressiveness of such states.

2022-12-08 | GSE211906 | GEO

Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma

Project description:Malignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix-loop-helix microphthalmia transcription factor (MITF) is the master regulator determining the identity and properties of the melanocyte lineage, and is regarded as a lineage-specific ‘oncogene’ that has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence. By combining chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) and RNA sequen- cing analyses, we show that MITF directly regulates a set of genes required for DNA replication, repair and mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and through defective replication and repair induces DNA damage, ultimately ending in cellular senescence. These findings reveal a lineage-specific control of DNA replication and mitosis by MITF, providing new avenues for therapeutic intervention in melanoma. The identification of MITF-binding sites and gene- regulatory networks establish a framework for under- standing oncogenic basic helix-loop-helix factors such as N-myc or TFE3 in other cancers. 4 samples corresponding to genomic occupancy profiling of MITF (Cl8), PolII (501Mel), H3K4me3 501Mel). Anti-HA ChIP-seq on untagged cell line (501Mel) was used as a control.

2014-12-13 | E-GEOD-64137 | biostudies-arrayexpress

Expression data from human metastatic melanoma cell lines

2014-06-10 | GSE56717 | GEO

Genomic Analysis Reveals Distinct Mechanisms and Functional Classes of SOX10-Regulated Genes in Melanocytes [ChIP-Seq]

Project description:We performed ChIP-Seq analysis of SOX10, histone H3 lysine 27 acetylation (H3K27ac) and H3K27 trimethylation (H3K27me3) in melanocytes to profile the genomic binding sites of SOX10 and the chromatin landscape. In parallel, we generated Sox10 haploinsufficient cell lines using gene knockout approaches and conducted microarray gene expression analysis to identify functional gene targets of SOX10 transcriptional regulation in melanocytes. We demonstrate that SOX10 predominantly engages “open” chromatin, binds to melanocyte enhancer elements and plays a central role in transcriptional activation and repression of functionally distinct classes of genes. Furthermore, we identified cis-regulatory sequence motifs of putative co-regulatory transcription factors that define SOX10-activated and SOX10-repressed target genes. Our results uncover novel mechanisms and roles of SOX10 in global transcriptional regulation of diverse regulatory pathways in the melanocyte lineage. ChIP-seq profiling of SOX10, H3K27ac, and H3K27me3 in the mouse melanocyte cell line melan-Ink4a-Arf-1 (melan-a).

2015-07-03 | E-GEOD-69949 | biostudies-arrayexpress

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