Understanding gene expression signatures with pigmentation changes in Melanocytes
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ABSTRACT:
PROVIDER: PRJNA420095 | ENA |
REPOSITORIES: ENA
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Project description:This microarray experiment was performed for identifying the signaling pathways that could be differentially regulated in response to changes in the pigmentation levels in human melanocytes. Melanocytes were either treated with pigmentation inducing agent or depigmenting compound targeting tyrosinase (key enzyme involved in the melanogenesis). The samples were then processed for analyzing the differentially regulated signaling pathway by performing microarray on agilent platform. The pathway enrichment analysis was executed on DAVID software. The plot has been generated using the average enrichment score for the pathways under similar category of function. Interestingly, along with the expected melanogenic and cAMP pathways, we observed differential regulation of Ca2+ signaling during pigmentation. We then performed several experiments for evaluating the contribution of cytoplasmic and endoplasmic reticulum (ER) Ca2+ homeostasis to pigmentation. After extensive studies in in vitro and in vivo pigmentation models, we demonstrate a critical role for ER Ca2+ sensor, STIM1 protein in the process of pigmentation. Taken together, we performed the microarray experiment for identifying potential pathways wherein Ca2+ homeostasis came out as one of the several hits. We then specifically studied cytoplasmic and endoplasmic reticulum (ER) Ca2+ homeostasis and identified a novel regulator of pigmentation based on several lines of evidences including in vivo model system
2018-01-03 | GSE107450 | GEO
Project description:Lineage-specific differentiation programs are activated by epigenetic changes in chromatin structure. Melanin-producing melanocytes maintain a gene expression program ensuring appropriate enzymatic conversion of metabolites into the pigment, melanin, and its transfer to surrounding cells. During neuroectodermal development, SMARCA4, the catalytic subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes, is essential for lineage specification. SMARCA4 is also required for development of multipotent neural crest precursors into melanoblasts, which differentiate into pigment-producing melanocytes. In addition to the catalytic domain, SMARCA4 and several SWI/SNF subunits contain bromodomains which are amenable to pharmacological inhibition. We investigated the effects of pharmacological inhibitors of SWI/SNF bromodomains on melanocyte differentiation. Strikingly, treatment of murine melanoblasts and human neonatal epidermal melanocytes with selected bromodomain inhibitors abrogated melanin synthesis and visible pigmentation. Using functional genomics, iBRD9, a small molecule selective for the bromodomain of BRD9, repressed pigmentation-specific gene expression. Depletion of BRD9 confirmed a requirement for expression of pigmentation genes in the differentiation program from melanoblasts into pigmented melanocytes and in melanoma cells. Chromatin immunoprecipitation assays showed that iBRD9 disrupts the occupancy of bromodomain containing 9 (BRD9) and the catalytic subunit SMARCA4. These data indicate that BRD9 promotes melanocyte differentiation and pigmentation whereas pharmacological inhibition of BRD9 is repressive.
2022-10-17 | GSE210015 | GEO
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from embryonic stem cells (ESCs), ESC-derived melanocyte progenitors, ESC-derived mature melanocytes, primary melanocytes, and disease-specific induced pluripotent stem cell-derived melanocytes.
2013-06-01 | E-GEOD-45226 | biostudies-arrayexpress
Project description:MITF, a gene that is mutated in familial melanoma and Waardenburg syndrome, encodes multiple isoforms expressed from alternative promoters that share common coding exons but have unique amino termini. It is not completely understood how these isoforms influence pigmentation in different tissues and how expression of these independent isoforms of MITF are regulated. Here, we show that melanocytes express two isoforms of MITF, MITF-A and MITF-M. Expression of MITF-A is partially regulated by a newly identified retinoid enhancer element located upstream of the MITF-A promoter. Mitf-A knockout mice have only subtle changes in melanin accumulation in the hair and reduced Tyr expression in the eye. In contrast, Mitf-M null mice have enlarged kidneys, lack neural crest derived melanocytes in the skin, choroid, and iris stroma; yet maintain pigmentation within the retinal pigment epithelium and iris pigment epithelium of the eye. Taken together, these studies identify a critical role for MITF-M in melanocytes, a minor role for MITF-A in regulating pigmentation in the hair and Tyr expression in the eye, and a novel role for MITF-M in size control of the kidney.
2019-12-31 | GSE138538 | GEO
Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders.
2013-06-01 | GSE45226 | GEO
Project description:Msh homeobox 1 (MSX1) is a transcription factor implicated in neural crest specification. Ectopic expression of MSX1 reprograms mature melanocytes into a neural crest-like state as a single factor. MSX1-reprogrammed melanocytes lose pigmentation and become multipotent. To identify immediate targets of MSX1, we generated a tetracycline-inducible system (Tet-ON) in order to express MSX1 in primary melanocytes (iMSX1) in a clean and rapid way starting at defined time points and perform a global gene expression analysis.
2016-09-30 | GSE56957 | GEO
Project description:Immortalized, amelanotic melanocytes isolted from skin of Balb/c express enzymatically-inactive tyrosinase due to a homozygous point mutation (TGT->TCT) in tyrosinase gene, resulting in a lack of melanin . To serve as a control cell line, pigmentation was restored in these cells by correcting the point mutation using an RNA-DNA oligonucleotide (kingly gift from Dr. Alexeev Y. Vitali). We used microarray to detail the effect of tyrosinase mutation on gene expression in normal versus mutant melanocytes. Pigmented and non-pigmented melanocytes were grown for RNA extraction and hybridization on Affymetrix microarrays. We used both normal and mutant melanocyte in order to obtain expression profiles. We then examined variances in gene expression between the two cell lines.
2013-09-21 | E-GEOD-51073 | biostudies-arrayexpress
Project description:SEMA3E-PLXND1 induced transcriptional changes in B16 melanocytes
| PRJNA783012 | ENA
Project description:Melanocytes are surrounded by diverse cells including sensory neurons in our skin, but their interaction and functional importance has been poorly investigated. In this study, we found that melanocytes and nociceptive neurons contact more in human skin color patch tissue than control. Co-culture with human iPS cell-derived sensory neurons significantly induced morphogenesis and pigmentation of human melanocytes. To reveal melanocytes-stimulating factors secreted from neurons, we performed proteomic analyses and identified RGMB in the sensory neuron-conditioned media. RGMB protein induced morphogenesis and melanin production of melanocytes, demonstrating that RGMB is a melanocyte-stimulating factor released from sensory neurons. Transcriptome analysis suggested that the melanosome transport machinery could be controlled by RGMB, which led us to identify vesicle production response of melanocytes upon RGMB treatment. This study discovered a role of sensory neurons to modulate multiple aspects of human melanocytes through secretion of a key factor RGMB.
2022-08-08 | GSE189493 | GEO
Project description:Damage to the gene regulatory network governing terminal differentiation of melanocytes leads to pigmentation phenotypes and increases the risk for melanoma. Microphthalmia-associated transcription factor (MITF) directly activates expression of melanocyte differentiation effectors, and levels of MITF have been proposed to govern the melanoma phenotype. Mutations in the gene encoding Transcription Factor Activator Protein 2 alpha (TFAP2A) cause reduced pigmentation in model organisms and premature hair graying in humans, and TFAP2A expression tends to be lower in advanced melanoma tumors than in benign nevi. However, the transcriptional targets of TFAP2A in melanocytes, and the epistatic relationship of TFAP2A and MITF, have been unclear. Using microarray-based analysis of zebrafish tfap2a mutant embryos, we generated a profile of genes whose expression is Tfap2a-dependent. We conducted anti-TFAP2A chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in immortalized mouse melanocytes and human primary melanocytes, and discovered that TFAP2A peaks are present near the promoters of Tfap2a-dependent genes expressed in melanocytes, and also at the majority of enhancers active in melanocytes. Comparison of TFAP2A ChIP-seq data to published MITF ChIP-seq data showed that the set of genes with promoters bound by both MITF and TFAP2A is enriched for the gene ontology term “pigment cell differentiation.” Deletion analysis of one such co-bound promoter, for Transient Receptor Potential Melastatin-like 1(TRPM1), confirmed that its expression depends on the presence of MITF binding sites as previously shown, but also depends on the presence of TFAP2A binding sites. Finally, we find that mitfa and tfap2a interact genetically in zebrafish. Collectively, these results show that TFAP2A, operating in parallel with MITF, directly regulates effectors of terminal differentiation in melanocytes and melanoma.
2017-02-17 | GSE72953 | GEO