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BMP signaling: at the gate between activated melanocyte stem cells and differentiation

ABSTRACT: BMP signaling: at the gate between activated melanocyte stem cells and differentiation

PROVIDER: PRJNA613693 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11359900_1.fastq.gz	Fastqsanger.gz
	SRR11359900_2.fastq.gz	Fastqsanger.gz
	SRR11360000_1.fastq.gz	Fastqsanger.gz
	SRR11360000_2.fastq.gz	Fastqsanger.gz
	SRR11360100_1.fastq.gz	Fastqsanger.gz

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BMP signaling: at the gate between activated melanocyte stem cells and differentiation [ATAC-seq]

Project description:Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single cell RNA-sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated during differentiation. Employing conditional lineage-specific genetic ablation studies in mice, we find that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream of activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and promoter analyses, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1 and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.

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Project description:Adult tissue stem cells protect their long-term potential by exerting precise control over their transitions between quiescence, activation, and differentiation. Through cyclic bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate to produce and transfer pigment to hair cells. The signaling factors orchestrating this process are still poorly understood. Here, we use single cell RNA-sequencing with pseudotime analysis to elucidate the transcriptional trajectory of McSCs through quiescence, activation, and differentiation into mature melanocytes. Unearthing signs of increased WNT and BMP signaling along this progression, we lineage-ablate either pathway and see hair graying. We show that BMP signaling functions downstream of McSCs but upstream of WNT signaling through LEF1. After stem cell activation, the two pathways trigger committed, proliferative progeny to fuel MITF-dependent differentiation. Analyses of the promoters required for melanosome maturation suggest a specific reliance upon MITF and LEF1 transcription factors, which we show are dampened without BMP signaling. Our findings shed light upon the signaling interplay that orchestrates the melanocyte lineage. Moreover, the block in differentiation and enhanced proliferation observed in the absence of BMP signaling raises the disconcerting possibility that BMP may harbor not only tumor promoting but also tumor suppressing activity in melanoma.

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