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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE64137 | GEO | 2014/12/13

SECONDARY ACCESSION(S): PRJNA270236

REPOSITORIES: GEO

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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

Regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Project description:The ability of cancer cells to switch phenotype in response to a dynamic intra-tumor microenvironment is a major barrier to effective therapy. In melanoma, down-regulation of the lineage addiction oncogene MITF (Microphthalmia-associated transcription factor) is a hallmark of the proliferative-to-invasive phenotype switch. Yet how MITF promotes proliferation and suppresses invasion is poorly understood. Here we show that expression of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) is activated by MITF, but suppressed by the stress-responsive transcription factor ATF4. SCD expression is required for MITF-positive melanoma cell proliferation,. By contrast, MITF-low cells express reduced levels of SCD and are insensitive to its inhibition, indicating that cell phenotype dictates response to drugs targeting lipid metabolism. Since SCD suppresses inflammatory signalling and ATF4 expression, the results identify a positive feedback-loop that can maintain an invasive phenotype, uncover a key role for MITF and ATF4 in metabolic reprograming, and reveal fatty acid composition as a driver of melanoma phenotype-switching.

2019-11-19 | PXD010254 | Pride

Local Genomic Features Predict the Distinct and Overlapping Binding Patterns of the bHLH‐Zip Family Oncoproteins MITF and MYC‐MAX

Project description:MITF and MYC are well‐known oncoproteins and members of the basic helix‐loop‐helix leucine zipper (bHLH‐Zip) family of transcription factors (TFs) recognizing hexamer E‐box motifs. MITF and MYC not only share the core binding motif, but are also the two most highly expressed bHLH‐Zip transcription factors in melanocytes, raising the possibility that they may compete for the same binding sites in select oncogenic targets. Mechanisms determining the distinct and potentially overlapping binding modes of these critical oncoproteins remain uncharacterized. We introduce computational predictive models using local sequence features, including a boosted convolutional decision tree framework, to distinguish MITF vs. MYC‐MAX binding sites with up to 80% accuracy genome wide. Select E‐box locations that can be bound by both MITF and MYC‐MAX form a separate class of MITF binding sites characterized by differential sequence content in the flanking region, diminished interaction with SOX10, higher evolutionary conservation, and less tissue‐specific chromatin organization.

2018-12-14 | GSE115845 | GEO

Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Project description:Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signalling, and an ATF4-mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.

2019-10-16 | GSE137390 | GEO

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

Project description:A basic helix-loop-helix transcription factors network mediates the brassinosteroid signal

| PRJNA221228 | ENA

Rattus norvegicus

Project description:Prg1 is regulated by the basic helix-loop-helix transcription factor Math2

| PRJNA105929 | ENA

MS23, a master basic helix-loop-helix factor in maize, regulates the birth and maturation of tapetum

Project description:A cascade of basic helix-loop-helix transcription factors guide tapetal cell development in maize anthers, using proteins conserved in Arabidopsis and rice but deployed with a distinctive timing. Anthers were dissected and staged to be 1500 μm in length (+/- 100 μm) and samples were compared between mutants and fertile siblings on an Agilent 4x44 custom microarray. Analysis included MS32 which is another basic helix-loop-helix factor that acts later during tapetal differentiation.

2016-12-31 | GSE90968 | GEO

Project description:The basic helix-loop-helix transcription factor SmbHLH1 represses anthocyanin biosynthesis in eggplant

| PRJNA761256 | ENA

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