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Understanding gene expression signatures with pigmentation changes in Melanocytes

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE107450 | GEO | 2018/01/03

SECONDARY ACCESSION(S): PRJNA420095

REPOSITORIES: GEO

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Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

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Understanding gene expression signatures with pigmentation changes in Melanocytes

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