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Transcriptional profiling of pancreatic somatostatin and beta-cells from zebrafish [bulk RNA-seq]

ABSTRACT: Transcriptional profiling of pancreatic somatostatin and beta-cells from zebrafish [bulk RNA-seq]

PROVIDER: PRJNA640144 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12037503.fastq.gz	Fastqsanger.gz
	SRR12037504.fastq.gz	Fastqsanger.gz
	SRR12037505.fastq.gz	Fastqsanger.gz
	SRR12037506.fastq.gz	Fastqsanger.gz
	SRR12037507.fastq.gz	Fastqsanger.gz

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Project description:A highly specific mosaic transcriptional environment guides the fate of pancreatic progenitors during development and next maintains the identity of mature endocrine cells. In mice, one of such transcription factors is MNX1 (motor neuron and pancreas homobox1). It is essential for beta cell development and identity as its deletion in mature beta cells increases their somatostatin expression via an unknown mechanism. Here, we asked whether MNX1 plays a similar role in human beta cells and dissected the molecular players involved in its function. We used the human beta cell line EndoC-BH1, knocked down MNX1 expression using siRNA and performed bulk RNA sequencing searching for MNX1 targets. We next performed loss- (siRNA) and gain- (transduction with lentivectors and lipofections) of function to determine how MNX1 regulates gene expression in human beta cells. SiRNA-mediated downregulation of MNX1 in EndoC-BH1 cells induced the upregulation of somatostatin as well as its transcriptional activator HHEX. RNAseq revealed PERCC1 (Proline and Glutamate Rich with Coiled Coil 1) as being among the highest upregulated genes. SiRNA-mediated loss of PERCC1 upon MNX1 knockdown impaired the upregulation of both SST and HHEX expression, while PERCC1 overexpression upregulated the expression of both HHEX and SST. PERCC1 expression was tightly regulated by HHEX and by its own expression in a positive feedback mechanism. Moreover, NKX2.2 downregulation, whose knockout in mice induces somatostatin upregulation, led to the upregulation of PERCC1, HHEX and SST in EndoC-BH1. Finally, over-expression of PERCC1 in primary mouse beta cells revealed an upregulation of both mouse Hhex and Sst. We discovered a novel MNX1-PERCC1-HHEX regulatory axis in human beta cells. There, MNX1 protects beta cell identity by inhibiting PERCC1, an activator of HHEX and SST expression. PERCC1 might thus be considered as a sharply tuned central hub for SST regulation. Our results increase our knowledge of beta cell plasticity and may have implications for therapeutic strategies aimed at protecting beta cell identity.

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Transcriptional profiling of pancreatic somatostatin and beta-cells from zebrafish [bulk RNA-seq]

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