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Role of transcription factor ONECUT1 during in vitro pancreatic differentiation of human pluripotent stem cells

ABSTRACT: Role of transcription factor ONECUT1 during in vitro pancreatic differentiation of human pluripotent stem cells

PROVIDER: PRJNA545052 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15711671.fastq.gz	Fastqsanger.gz
	SRR15711672.fastq.gz	Fastqsanger.gz
	SRR9133810.fastq.gz	Fastqsanger.gz
	SRR9133940_1.fastq.gz	Fastqsanger.gz
	SRR9133940_2.fastq.gz	Fastqsanger.gz

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Role of transcription factor ONECUT1 (HNF6) during in vitro pancreatic differentiation of human pluripotent stem cells [ATAC-seq]

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Role of transcription factor ONECUT1 (HNF6) during in vitro pancreatic differentiation of human pluripotent stem cells [RNA-seq]

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Mutations and variants of ONECUT1 in diabetes

Project description:Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.

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A transcriptional and open chromatin landscape and the role of ONECUT1 in human pancreas differentiation [RNA-seq]

Project description:Pancreatic differentiation and specification of lineages is a tightly controlled process involving a interconnected network of transcriptional regulation. Although more knowledge on human pancreatic development is accumulating, the precise role of many transcription factors is only described in mouse. Therefore, it is of great interest to expand our knowledge using alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells. Here, we provide stage-specific data from RNA-, ChIP-, and ATAC-sequencing to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreas differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreas transcription factors and determine ONECUT1 as a crucial regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification.Our approach of dissecting the transcriptional and regulatory mechanisms revealed an important role for the specific key player ONECUT1 and will help to better understand human development and disease.

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A transcriptional and open chromatin landscape and the role of ONECUT1 in human pancreas differentiation [ATAC-seq]

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Project description:We have identified HNF6 as an essential transcription factor for endocrine pancreatic development. HNF6 binds to and possibly regulates other isletogenesis transcription factors, driving endocrine differentiation. ATAC sequencing of control and HNF6-depleted hESC during in vitro pancreatic differentiation will help to understand the regulatory mechanisms during cell fate decisions.

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Role of transcription factors ONECUT1 (HNF6), GATA6 and NKX6.1 during in vitro pancreatic differentiation of human pluripotent stem cells.

Project description:Role of transcription factors ONECUT1 (HNF6), GATA6 and NKX6.1 during in vitro pancreatic differentiation of human pluripotent stem cells.

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CRISPR Screening Uncovers a Long-Range Enhancer for ONECUT1 in Pancreatic Differentiation and Links a Diabetes Risk Variant [Hi-C]

Project description:Functional enhancer annotation is a valuable first step for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants for investigation. However, unbiased enhancer discovery in physiologically relevant contexts remains a major challenge. To discover regulatory elements pertinent to diabetes, we conducted a CRISPR interference (CRISPRi) screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers uncovered, we focused on a long-range enhancer ~664 kb from the ONECUT1 promoter, as coding mutations in ONECUT1 cause pancreatic hypoplasia and neonatal diabetes. Homozygous enhancer deletion in hPSCs was associated with a near-complete loss of ONECUT1 gene expression and compromised pancreatic differentiation. This enhancer contains a confidently fine-mapped type 2 diabetes (T2D) associated variant (rs528350911) which disrupts a GATA motif. Introduction of the risk variant into hPSCs revealed substantially reduced binding of key pancreatic transcription factors (GATA4, GATA6 and FOXA2) on the edited allele, accompanied by a slight reduction of ONECUT1 transcription, supporting a causal role for this risk variant in metabolic disease. This work expands our knowledge about transcriptional regulation in pancreatic development through the characterization of a long-range enhancer and highlights the utility of enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

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