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Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets

ABSTRACT: Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets

PROVIDER: PRJNA665465 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12704300.fastq.gz	Fastqsanger.gz
	SRR12704225_1.fastq.gz	Fastqsanger.gz
	SRR12704225_2.fastq.gz	Fastqsanger.gz
	SRR12704226_1.fastq.gz	Fastqsanger.gz
	SRR12704226_2.fastq.gz	Fastqsanger.gz

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Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (RNA-seq)

Project description:The transcription factor Nfatc2 is a potent β-cell mitogen in mouse and human islets, however, the direct genomic targets that mediate the mitogenic effects have not been identified. We expressed a constitutively active form of Nfatc2, and the closely related Nfatc1, in human islets and identified ~5,600 differentially expressed genes. Nfatc2 binding sites in human islets were identified via ChIP-seq, yielding ~8,600 high-confidence peaks. By integrating gene expression changes induced by Nfatc2 with genomic binding sites for Nfatc2, we identified ~2,200 direct transcriptional targets of Nfatc2 in human islets. Direct targets that were induced by Nfatc2 were enriched for transcripts that regulate the cell cycle, and for motifs associated with the transcription factor FoxP1. We showed that islets from an endocrine-specific FoxP1, FoxP2 and FoxP4 triple-knockout mouse are less responsive to Nfatc2-induced β-cell proliferation, suggesting the FoxP family may work in concert with Nfatc2 to regulate β-cell proliferation. Nfatc2 induced β-cell proliferation in both mouse and human islets, whereas Nfatc1 does so only in human islets. Exploiting this species difference in Nfatc1-responsiveness, we identified ~250 direct transcriptional targets with similar transcriptional profiles. This gene set strongly enriches for cell cycle-associated transcripts, and includes the nuclear hormone receptor, Nr4a1. We show that deletion of Nr4a1 greatly reduces the capacity of Nfatc2 to induce β-cell proliferation, suggesting that much of the effect on Nfatc2 occurs through its induction of Nr4a1. Integration of ncRNA profiling, chromatin accessibility and Nfatc2 binding sites enabled us to identify key Nfatc2-dependent enhancer loci that mediate enhanced β-cell proliferation.

2021-09-15 | GSE158498 | GEO

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ncRNA-seq)

2021-09-15 | GSE158497 | GEO

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ChIP-seq)

2021-09-15 | GSE158496 | GEO

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ATAC-seq)

2021-09-15 | GSE158495 | GEO

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ATAC-seq)

Project description:Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ATAC-seq)

| PRJNA665470 | ENA

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ncRNA-seq)

Project description:Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ncRNA-seq)

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Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ChIP-seq)

Project description:Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (ChIP-seq)

| PRJNA665469 | ENA

Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (RNA-seq)

Project description:Identification of direct transcriptional targets of Nfatc2 that promote β-cell proliferation in human islets (RNA-seq)

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Identification of direct transcriptional targets of NFATC2 that promote β cell proliferation.

Project description:The transcription factor NFATC2 induces β cell proliferation in mouse and human islets. However, the genomic targets that mediate these effects have not been identified. We expressed active forms of Nfatc2 and Nfatc1 in human islets. By integrating changes in gene expression with genomic binding sites for NFATC2, we identified approximately 2200 transcriptional targets of NFATC2. Genes induced by NFATC2 were enriched for transcripts that regulate the cell cycle and for DNA motifs associated with the transcription factor FOXP. Islets from an endocrine-specific Foxp1, Foxp2, and Foxp4 triple-knockout mouse were less responsive to NFATC2-induced β cell proliferation, suggesting the FOXP family works to regulate β cell proliferation in concert with NFATC2. NFATC2 induced β cell proliferation in both mouse and human islets, whereas NFATC1 did so only in human islets. Exploiting this species difference, we identified approximately 250 direct transcriptional targets of NFAT in human islets. This gene set enriches for cell cycle-associated transcripts and includes Nr4a1. Deletion of Nr4a1 reduced the capacity of NFATC2 to induce β cell proliferation, suggesting that much of the effect of NFATC2 occurs through its induction of Nr4a1. Integration of noncoding RNA expression, chromatin accessibility, and NFATC2 binding sites enabled us to identify NFATC2-dependent enhancer loci that mediate β cell proliferation.

| S-EPMC8553569 | biostudies-literature

Genome-wide RNA-sequencing of mouse islets 48 hour after transduction with adenoviruses expressing either GFP (control), or constitutively active forms of the transcription factors, Nfatc1 or Nfatc2.

Project description:Genetic variation at ~160 gene loci is associated with type 2 diabetes (T2D). Using an F2 mouse intercross segregating for T2D, we searched for a driver of GWAS gene expression and found that ~40% of the GWAS genes are regulated in trans by a locus on chromosome 2 in islets. We identified Nfatc2 as a candidate driver of GWAS gene expression. Overexpression of Nfatc2 induced β-cell proliferation in mouse and human islets. We show that many T2D GWAS genes are responsive to NFAT and thus may act coordinately as intermediate traits to promote diabetes.

2016-11-17 | GSE73697 | GEO

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