Pancreatic Islet Transcriptional Enhancers and Diabetes

Cebola, Inês

doi:10.1007/s11892-019-1230-6

Cited by 12 publications

(9 citation statements)

References 102 publications

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“…Genome wide association studies (GWAS) to date have identified >240 loci that modulate risk for T2D (Mahajan et al 2018). However, these SNPs mostly occur in non protein-coding regions and are highly enriched to overlap islet-specific enhancer regions (Parker et al 2013;Pasquali et al 2014;Quang et al 2015;Thurner et al 2018;Cebola 2019). These findings suggest the variants likely affect gene expression rather than directly altering protein structure or function.…”

Section: Introductionmentioning

confidence: 99%

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures

et al. 2021

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Identifying the tissue-specific molecular signatures of active regulatory elements is critical to understand gene regulatory mechanisms. Active enhancers can be transcribed into enhancer RNA. Here, we identify transcription start sites (TSS) using cap analysis of gene expression (CAGE) across 71 human pancreatic islet samples. We identify 9,954 CAGE tag clusters (TCs) in islets, ~20% of which are islet-specific and occur mostly distal to known gene TSSs. We integrated islet CAGE data with histone modification and chromatin accessibility profiles to identify epigenomic signatures of transcription initiation. Using a massively parallel reporter assay, we observe significant enhancer activity (5% FDR) for 2,279 of 3,378 (~68%) tested CAGE elements. TCs within accessible enhancers show higher enrichment to overlap type 2 diabetes genome-wide associated loci than existing accessible enhancer annotations, which emphasizes the utility of mapping CAGE profiles in disease-relevant tissue. This work provides a high-resolution transcriptional regulatory map of human pancreatic islets with utility for dissecting functional enhancers at GWAS loci..

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Section: Introductionmentioning

confidence: 99%

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures

et al. 2021

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“…Notably, monogenic diabetes predominantly results from mutations in transcription factors, which are involved in pancreas development 4 . Moreover, genetic variants in or nearby some of these transcription factor genes have been associated with type 2 diabetes risk 5 .…”

Section: Introductionmentioning

confidence: 99%

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Mueller,

Isaacson,

Wilson

et al. 2024

Nat Commun

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Missense variants are the most common type of coding genetic variants. Their functional assessment is fundamental for defining any implication in human diseases and may also uncover genes that are essential for human organ development. Here, we apply CRISPR-Cas9 gene editing on human iPSCs to study a heterozygous missense variant in GLI2 identified in two siblings with early-onset and insulin-dependent diabetes of unknown cause. GLI2 is a primary mediator of the Hedgehog pathway, which regulates pancreatic β-cell development in mice. However, neither mutations in GLI2 nor Hedgehog dysregulation have been reported as cause or predisposition to diabetes. We establish and study a set of isogenic iPSC lines harbouring the missense variant for their ability to differentiate into pancreatic β-like cells. Interestingly, iPSCs carrying the missense variant show altered GLI2 transcriptional activity and impaired differentiation of pancreatic progenitors into endocrine cells. RNASeq and network analyses unveil a crosstalk between Hedgehog and WNT pathways, with the dysregulation of non-canonical WNT signaling in pancreatic progenitors carrying the GLI2 missense variant. Collectively, our findings underscore an essential role for GLI2 in human endocrine development and identify a gene variant that may lead to diabetes.

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“…However, gene expression represents the final outcome of a complex layer of genetic and epigenetic factors that determine islet cell fate [7][8][9] and identity [10,11]. Previous studies have explored pancreatic islet cellular identity by evaluating epigenomic features such as methylation [12][13][14], histone modifications [15][16][17][18], and enhancer regulatory regions [19][20][21][22][23][24]. While each of these factors contributes to defining and maintaining cell fate and identity, connecting chromatin accessibility differences to epigenetic factors promises to provide further insight into outstanding questions within the field.…”

Section: Introductionmentioning

confidence: 99%

Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers

2023

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Background High throughput sequencing has enabled the interrogation of the transcriptomic landscape of glucagon-secreting alpha cells, insulin-secreting beta cells, and somatostatin-secreting delta cells. These approaches have furthered our understanding of expression patterns that define healthy or diseased islet cell types and helped explicate some of the intricacies between major islet cell crosstalk and glucose regulation. All three endocrine cell types derive from a common pancreatic progenitor, yet alpha and beta cells have partially opposing functions, and delta cells modulate and control insulin and glucagon release. While gene expression signatures that define and maintain cellular identity have been widely explored, the underlying epigenetic components are incompletely characterized and understood. However, chromatin accessibility and remodeling is a dynamic attribute that plays a critical role to determine and maintain cellular identity. Results Here, we compare and contrast the chromatin landscape between mouse alpha, beta, and delta cells using ATAC-Seq to evaluate the significant differences in chromatin accessibility. The similarities and differences in chromatin accessibility between these related islet endocrine cells help define their fate in support of their distinct functional roles. We identify patterns that suggest that both alpha and delta cells are poised, but repressed, from becoming beta-like. We also identify patterns in differentially enriched chromatin that have transcription factor motifs preferentially associated with different regions of the genome. Finally, we not only confirm and visualize previously discovered common endocrine- and cell specific- enhancer regions across differentially enriched chromatin, but identify novel regions as well. We compiled our chromatin accessibility data in a freely accessible database of common endocrine- and cell specific-enhancer regions that can be navigated with minimal bioinformatics expertise. Conclusions Both alpha and delta cells appear poised, but repressed, from becoming beta cells in murine pancreatic islets. These data broadly support earlier findings on the plasticity in identity of non-beta cells under certain circumstances. Furthermore, differential chromatin accessibility shows preferentially enriched distal-intergenic regions in beta cells, when compared to either alpha or delta cells.

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Pancreatic Islet Transcriptional Enhancers and Diabetes

Cited by 12 publications

References 102 publications

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures

A Transcription Start Site Map in Human Pancreatic Islets Reveals Functional Regulatory Signatures

Heterozygous missense variant in GLI2 impairs human endocrine pancreas development

Chromatin accessibility differences between alpha, beta, and delta cells identifies common and cell type-specific enhancers

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