SASH1 S519N variant links skin hyperpigmentation and premature hair graying to dysfunction of melanocyte lineage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1106514 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28850901.fastq.gz | Fastqsanger.gz | |||
| SRR28850902.fastq.gz | Fastqsanger.gz | |||
| SRR28850903.fastq.gz | Fastqsanger.gz | |||
| SRR28850904.fastq.gz | Fastqsanger.gz | |||
| SRR28850905.fastq.gz | Fastqsanger.gz |
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Project description:A better understanding of human melanocyte and melanocyte stem cell (McSC) biology is essential for treating melanocyte-related diseases. This study employed an inherited pigmentation disorder carrying the SASH1S519N variant in a Hispanic family to investigate the SASH1 function in melanocyte lineage and the underlying mechanism for this disorder. We used a multidisciplinary approach, including clinical exams, human cell assays, yeast two-hybrid screening, and biochemical techniques. Results linked early hair graying to the SASH1S519N variant, a previously unrecognized clinical phenotype in hyperpigmentation disorders. We identified SASH1 as a novel regulator in McSC maintenance and discovered that TNKS2 is crucial for SASH1’s role in vitro. Additionally, the S519N variant is located in one of multiple tankyrase binding motifs and alters the binding kinetics and affinity of the interaction. In summary, this disorder showcases accelerated aging in human McSC, linking both gain and loss of pigmentation to McSC dysfunction in the same individuals. The findings offer new insights into the roles of SASH1 and TNKS2 in McSC maintenance and the molecular mechanisms of pigmentation disorders. We propose that a comprehensive clinical evaluation of patients with skin disorders should include an assessment and history of hair pigmentation loss.
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Project description:The incidence of diseases, including cancer, increases with age. While age-associated diseases with stem cell exhaustion are potentially antagonistic to cancer development1, the relationship between those is still largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately govern the antagonism between poliosis (hair graying) and melanoma. We found that McSCs undergo senescence-associated differentiation (seno-differentiation) in response to DNA double strand breaks (DSBs) such as by ionizing radiation (IR) and ageing upon their activation for self-renewal, leading to their depletion and resultant hair graying at the cost of cancer protection. RNA-seq and functional analysis of the skin exposed to different types of genotoxic stress revealed that activation of the p53-p21 axis and TBK1 pathway by DSBs within McSCs causes their depletion. Comparative analysis of the young vs. aged stem cell niche identified the KIT ligand (KITL/SCF) as a master niche factor for McSC self-renewal. Strikingly, co-exposure of the irradiated skin to carcinogens rescued hair graying by augmenting the secretory phenotype of niche cells to repress McSC seno-differentiation through the dual activation of KIT signaling and arachidonic acid pathway in McSCs. Collectively, our data provide concrete evidence for the phenotypic trade-off between ageing and cancer based on the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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Project description:The exposome, an individual’s lifelong environmental exposure, profoundly impacts health. Somatic tissues undergo functional decline with age, exhibiting characteristic ageing phenotypes including hair graying and cancer. However, the specific genotoxins, signals and cellular mechanisms underlying each phenotype remain largely unknown. Here, we report that melanocyte stem cells (McSCs) and their niche coordinately determine individual stem cell fate through antagonistic, stress-responsive pathways, depending on the type of genotoxic damage incurred. McSC fate-tracking in mice revealed that McSCs undergo cellular senescence-associated differentiation (seno-differentiation) in response to DNA double-strand breaks (DSBs), resulting in their selective depletion and hair graying, and effectively protecting against melanoma. Conversely, carcinogens can suppress McSC seno-differentiation, even in DSB-harboring cells, by activating arachidonic acid metabolism and the niche-derived KIT ligand, thereby promoting McSC self-renewal. Collectively, the fate of individual stem cell clones - expansion versus exhaustion - cumulatively and antagonistically governs ageing phenotypes through interaction with the niche.
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