Identification of hypoxia-induced HIF1A targets in melanocytes reveals a molecular profile associated with poor prognosis for melanoma [ChIP-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86554 | GEO | 2017/02/20
SECONDARY ACCESSION(S): PRJNA342187
REPOSITORIES: GEO
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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. These results indicated that SOX10 plays a role in activation and repression of distinct classes of genes. Microarray gene expression analysis in Sox10 haploinsufficient immortal melanocyte cell lines derived from 3-day-old Sox10LacZ/+; Ink4a-Arf null mice. Syngeneic control cells were melan-Ink4a-Arf-1.
2015-07-03 | E-GEOD-69860 | biostudies-arrayexpress
Project description:Gene expression profiling of tissues derived from different genetic backgrounds can provide insight to potential phenotype-related changes in gene expression. We have compared wildtype C57BL/6 (melan-Ink4a) melanocyte cell gene expression to that of, âbrownâ Tyrp1b/ b (melan-Ink4a-b) and âchocolateâ Rab38 cht/cht (melan-cht) melanocyte derived lines. We observed alterations in gene expression consistent with a physiological response of melan-Ink4a-b cells to endoplasmic reticulum protein-folding impairment. Additionally, a set of loci was identified that are expressed in a similar manner to known melanocyte genes. Importantly, the collection of 254 genes is enriched for expression in the multiple melanocyte lines relative to control cell populations. This set contains Tyr, Tyrp1, Dct, Si, Melna, Slc24a5, Slc45a2, Slc24a4, Mitf, and Sox10, in addition to genes not previously attributed to pigmentation and genes with unknown function. Further evaluation of one gene in this cohort, Gpnmb, demonstrated an expression pattern similar to Dct, Si and Mitf. This expression is vastly reduced in MitfMi mutants embryos, indicating that it is dependent on Mitf for in vivo expression. Consistent with this notion, a highly-conserved MITF binding site resides directly upstream of human GPNMB, and deletion of this sequence dramatically reduces in vitro enhancer activity. Keywords: NIH embryo fibroblast cell line, melanocyte cell line, Ink4a, Tyrp1b, Rab38 A 32k expression arrays were generated by printing Oligo nucleotides from Operon Mouse oligo set (MV3) onto epoxy slides. Total RNA from immortalized melanocyte cell lines derived from C57BL/6J Ink4a-/- (melan-Ink4a-1), C57BL/6J Ink4a-/-; Tyrp1b/b (melan-Ink4a-b) and 2 separate C57BL/6J Ink4a-/-; RaB38cht/cht lines (melan-cht4), (melan-cht5) and NIH3T3 were labeled with Cy5/3 and co-hybridized with a total RNA universal reference (Stratagene, Inc) labeled with Cy3/5. Each comparison was done in Triplicate including one dye swap.
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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
Project description:The melan-a cell line is derived from immortalized mouse melanocytes obtained from Ink4a-ARF-/- mice. RNA-seq was performed to assess the global nature of transcript and gene expression profiles in melan-a cells. These RNA-seq data, along with separate ChIP-seq performed in melan-a cells (GSE38498), were used to correlate gene expression patterns with the presence or absence of transcription factors of interest.
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Project description:These datasets describe a melanocyte specific, HIF1A-Dependent / Hypoxia-Responsive gene expression signature defined by the regulation of genes critical to metabolism, chromatin and transcriptional regulation, vascularization and cellular invasivness. These genes provide lineage specific targets for refinement of diagnostic markers associated with primary melanoma tumor metastatic potential, and also provides novel molecular targets for therapeutic strategies targeting metastatic disease progression.
2017-02-20 | GSE86553 | GEO
Project description:Gene expression profiling of tissues derived from different genetic backgrounds can provide insight to potential phenotype-related changes in gene expression. We have compared wildtype C57BL/6 (melan-Ink4a) melanocyte cell gene expression to that of, “brown“ Tyrp1b/ b (melan-Ink4a-b) and “chocolate” Rab38 cht/cht (melan-cht) melanocyte derived lines. We observed alterations in gene expression consistent with a physiological response of melan-Ink4a-b cells to endoplasmic reticulum protein-folding impairment. Additionally, a set of loci was identified that are expressed in a similar manner to known melanocyte genes. Importantly, the collection of 254 genes is enriched for expression in the multiple melanocyte lines relative to control cell populations. This set contains Tyr, Tyrp1, Dct, Si, Melna, Slc24a5, Slc45a2, Slc24a4, Mitf, and Sox10, in addition to genes not previously attributed to pigmentation and genes with unknown function. Further evaluation of one gene in this cohort, Gpnmb, demonstrated an expression pattern similar to Dct, Si and Mitf. This expression is vastly reduced in MitfMi mutants embryos, indicating that it is dependent on Mitf for in vivo expression. Consistent with this notion, a highly-conserved MITF binding site resides directly upstream of human GPNMB, and deletion of this sequence dramatically reduces in vitro enhancer activity. Keywords: NIH embryo fibroblast cell line, melanocyte cell line, Ink4a, Tyrp1b, Rab38
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Project description:NRG1/ERBB3 signaling in melanocyte Melan-Ink4a cells
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Project description:We compared the transformation efficiencies of mutant NRAS and KRAS in immortal, non-transformed Ink4a/Arf-deficient melanocytes. NRAS mutation leads to increased cellular proliferation and is potently tumorigenic. In contrast, KRAS mutation does not enhance melanocyte proliferation and is only weakly tumorigenic on its own. While both NRAS and KRAS activate MAPK signaling, only NRAS enhances MYC activity in these cells. Our data suggests that the activity of specific RAS isoforms is context dependent and provides a possible explanation for the prevalence of NRAS mutations in melanoma.In addition, understanding this mechanism will have important implications for cancer therapies targeting RAS pathways. Keywords: RAS isoforms
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Project description:To investigate the molecular mechanism of the hypopigmentation observed in Dicer KO mice, Dicer knockdown was realised in vitro in normal C57BL/6 mouse melanocyte Melan-a cells. Transient transfection of Melan-a cells with siRNA directed against Dicer reduced Dicer protein levels to approximately 40% of that of siScr Melan-a cells 48 hours after transfection. We analyzed the transcriptome of Melan-a cells 48 hours after transfection with siDicer or siScr to understand the molecular mechanisms involved in Dicer-dependent melanocyte migration.
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