Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

Miguel-Escalada, Irene; Bonàs-Guarch, Sílvia; Cebola, Inês; Ponsa-Cobas, Joan; Mendieta-Esteban, Julen; Atla, Goutham; Javierre, Biola M.; Rolando, Delphine; Farabella, Irene; Morgan, Claire C.; García-Hurtado, Javier; Beucher, Anthony; Morán, Ignasi; Pasquali, Lorenzo; Ramos-Rodríguez, Mireia; Appel, Emil V. R.; Linneberg, Allan; Gjesing, Anette P.; Witte, Daniel R.; Pedersen, Oluf; Grarup, Niels; Ravassard, Philippe; Torrents, David; Mercader, Josep M.; Piemonti, Lorenzo; Berney, Thierry; Koning, Eelco J.P. de; Kerr–Conte, Julie; Pattou, François; Fedko, Iryna O.; Groop, Leif; Prokopenko, Inga; Hansen, Torben; Martí‐Renom, Marc A.; Fraser, Peter; Ferrer, Jorge

doi:10.1038/s41588-019-0457-0

Cited by 219 publications

(399 citation statements)

References 79 publications

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“…Here we used H3K27ac HiChIP, a novel technique that allows combined analysis of both chromatin conformation and chromatin activity, to create the first global study of promoter-enhancer interactions in keratinocytes and tissue resident CD8 + T cells. Equivalent data has so far only been generated in immune cells with few examples in other cell populations, such as HiChIP in endometrial cancer cells (O'Mara, Spurdle and Glubb 2019), and promoter-capture Hi-C in neuronal cells (Song et al 2019), cardiomyocytes (Choy et al 2018) and pancreatic islets (Miguel-Escalada et al 2019). A common limitation of these studies is that they make use of immortalized cell lines or differentiated pluripotent stem cells.…”

Section: Discussionmentioning

confidence: 99%

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Shi

Ray-Jones

Ding

et al. 2020

Preprint

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In the last 15 years Genome wide association studies (GWAS) have uncovered the genetic factors that contribute to disease risk for many disorders, yet the biological significance of many of these associations remain unclear. This is because about 90% of these variants are predicted to affect regulatory elements that are highly cell-type specific and can affect distal genes through chromatin interaction mechanisms and, therefore, understanding their role in disease is challenging.Previous studies have attempted to use chromatin conformation methods to describe the functional mechanism in disease associated loci. However, the majority of these studies have focused on cell lines derived from blood, which might not be the most relevant cell lines for dermatological conditions.Here, we generated HiChIP for H3K27ac, Hi-C and RNA-seq datasets from a keratinocyte and a skinplaque derived CD8+ T cell line. We studied their active chromatin conformation with the aim to identify biological mechanisms that could be affected by variants associated with skin related diseases: psoriasis (Ps), psoriatic arthritis (PsA), systemic sclerosis (SSc), melanoma and atopic dermatitis.In our analysis we show that HiChIP interactions provide functional evidence for gene regulation by showing that enhancers linked to genes that respond to IFN-γ stimulation are strongly enriched for motifs for TFs related to the stimulation. We also show that by using chromatin conformation we can recall 53% of eQTLs identified by GTEx in skin.In addition to our datasets, we integrated public datasets for a B cell-like lymphoblastoid cell line and primary CD4+ T cells to expand our analysis to include GWAS variants associated with the aforementioned diseases likely to be mediated specifically by B cells and CD4+ T cells (such as in systemic sclerosis and melanoma). We then identified the numerous genes that interact with GWAS variants associated and show that these genes strongly enrich for pathways that are related to the trait studied. For example, the top enriched pathways for autoimmune conditions such as PsA and psoriasis included responses to cytokines and T cell regulation, whereas for melanoma they were related to replicative senescence.We show examples of how our analysis can inform changes in the current description of a few psoriasis associated risk loci. For example, the variant rs10794648, which had previously been assigned to IFNLR1, was linked to GRHL3 in our dataset, a gene essential in skin repair and development. This can indicate a renewed importance of skin related factors in the risk of disease.In conclusion, this study allows us to further characterize disease risk loci by using novel chromatin conformation techniques, which can help identify the genes that are putatively involved in disease and has the potential to identify therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Shi

Ray-Jones

Ding

et al. 2020

Preprint

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“…Positional analyses also pointed out EIF3CL since its gene body was split by the inversion breakpoint. This gene is an excellent candidate given that some of its isoforms were preferentially expressed in human pancreatic islets 31 .…”

Section: Discussionmentioning

confidence: 99%

“…For the positional analysis, several annotations were gathered from the following sources: TAD boundaries from the Human ES Cell (H1) topologial domains 42 ; promoters, enhancers, CTCF-peaks and ATAC-seq open-chromatin regions from the human islet regulome annotation 43 ; islet-specificity scores were calculated using the gene expression data from 31 ; eQTL snp-gene associations from 41,44 .…”

Section: Positional Analysesmentioning

confidence: 99%

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Polymorphic inversions underlie the shared genetic susceptibility to prevalent common diseases

González

2019

Preprint

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The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed the largest inversion association analysis to date, including 21 inversions and 25 obesity-related traits, on a total of 408,898 Europeans, and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2 and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes of obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.

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“…Represented data corresponds to consolidated tracks released by Miguel-Escalada et al Details on number of samples per track are available (Miguel-Escalada et al, 2019). Previously published human islet RNA-seq (Morán et al, 2012), chromatin interaction maps (Miguel-Escalada et al, 2019a) were visualized on the WashU Epigenome browser using this session link: http://epigenomegateway.wustl.edu/browser/?genome=hg19&session=62hGf7nfcS&statusId =140947077. For pcHi-C interactions, only interactions with a CHiCAGO score > 5 were taken as high-confidence interactions, as previously described (Miguel-Escalada et al, 2019).…”

Section: Human Islet Regulome and Interactome Analysismentioning

confidence: 99%

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

Cebola

Carrat

et al. 2020

Preprint

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Genome-wide association studies have identified thousands of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of an associated enhancer, in human pancreatic beta cells impaired glucosestimulated insulin secretion. Expression of both STARD10 and FCHSD2, but not ARAP1, was reduced in cells harboring CRISPR deletions, and expression of STARD10 and FCHSD2 was associated with the possession of variant alleles in human islets. Finally, CRISPR-Cas9mediated loss of STARD10 or FCHSD2 impaired regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence β cell function.

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Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes

Cited by 219 publications

References 79 publications

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

An active chromatin interactome in relevant cell lines elucidates biological mechanisms at genetic risk loci for dermatological traits

Polymorphic inversions underlie the shared genetic susceptibility to prevalent common diseases

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

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