Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression

Fasolino, Maria; Goldman, Naomi; Wang, Wenliang; Cattau, Benjamin; Zhou, Yeqiao; Petrović, Jelena; Link, Verena M.; Coté, Allison; Chandra, Aditi; Silverman, Michael A.; Joyce, Eric F.; Little, Shawn C.; Kaestner, Klaus H.; Naji, Ali; Raj, Arjun; Henao‐Mejia, Jorge; Faryabi, Robert B.; Vahedi, Golnaz

doi:10.1016/j.immuni.2020.01.003

Cited by 49 publications

(56 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As an example of how these techniques can be combined, a recent study compared chromatin accessibility (assay for transposase-accessible chromatin [ATAC]), CTCF occupancy and chromatin conformation in thymocytes from a T1D mouse model (NOD) and diabetes-resistant mice ( 51 ). The authors identified a higher number of chromatin interactions in the Idd T1D locus in NOD mice and analyzed this and other hyper-connected diabetes-specific 3D niches in depth, using fluorescence-microscopy and HiChIP.…”

Section: Making Contactmentioning

confidence: 99%

Functional genomics in autoimmune diseases

Ding

Frantzeskos

Orozco

2020

Human Molecular Genetics

View full text Add to dashboard Cite

Associations between genetic loci and increased susceptibility to autoimmune disease have been well characterized, however, translating this knowledge into mechanistic insight and patient benefit remains a challenge. While improvements in the precision, completeness and accuracy of our genetic understanding of autoimmune diseases will undoubtedly be helpful, meeting this challenge will require two interlinked problems to be addressed: first which of the highly correlated variants at an individual locus is responsible for increased disease risk, and second what are the downstream effects of this variant. Given that the majority of loci are thought to affect non-coding regulatory elements, the second question is often reframed as what are the target gene(s) and pathways affected by causal variants. Currently, these questions are being addressed using a wide variety of novel techniques and datasets. In many cases, these approaches are complementary and it is likely that the most accurate picture will be generated by consolidating information relating to transcription, regulatory activity, chromatin accessibility, chromatin conformation and readouts from functional experiments, such as genome editing and reporter assays. It is clear that it will be necessary to gather this information from disease relevant cell types and conditions and that by doing so our understanding of disease etiology will be improved. This review is focused on the field of autoimmune disease functional genomics with a particular focus on the most exciting and significant research to be published within the last couple of years.

show abstract

Section: Making Contactmentioning

confidence: 99%

Functional genomics in autoimmune diseases

Ding

Frantzeskos

Orozco

2020

Human Molecular Genetics

View full text Add to dashboard Cite

show abstract

“…In their recent publication, Montefiori et al linked 1999 cardiovascular disease-associated SNPs to 347 target genes in human-induced pluripotent stem cell derived cardio-myocytes, remarkably showing that 90% of variants did not target the nearest gene [ 80 ]. More recently, a group has shown that genetic variants associated with Type 1 Diabetes alter the chromatin conformation at disease-associated loci in a mouse model [ 84 ].…”

Section: Using Chromatin Conformation Methods To Map Target Genesmentioning

confidence: 99%

Using functional genomics to advance the understanding of psoriatic arthritis

et al. 2020

View full text Add to dashboard Cite

Psoriatic arthritis (PsA) is a complex disease where susceptibility is determined by genetic and environmental risk factors. Clinically, PsA involves inflammation of the joints and the skin, and, if left untreated, results in irreversible joint damage. There is currently no cure and the few treatments available to alleviate symptoms do not work in all patients. Over the past decade, genome-wide association studies (GWAS) have uncovered a large number of disease-associated loci but translating these findings into functional mechanisms and novel targets for therapeutic use is not straightforward. Most variants have been predicted to affect primarily long-range regulatory regions such as enhancers. There is now compelling evidence to support the use of chromatin conformation analysis methods to discover novel genes that can be affected by disease-associated variants. Here, we will review the studies published in the field that have given us a novel understanding of gene regulation in the context of functional genomics and how this relates to the study of PsA and its underlying disease mechanism.

show abstract

“…Interestingly, an analogous approach has also been used by Fasolino et al. [ 90 ] that added another layer of transcriptional regulation consisting of the linear and 3D organisation of the genome [ 90 ] aimed to study the impact of genetic variation associated with T1D on the 3D chromatin topology of T lymphocytes using a genetic model of T1D, the non-obese-diabetic (NOD) mouse strain. To elucidate the effects of genetic susceptibility, they used diabetes-susceptible NOD and diabetes-resistant C57BL/6 mice (as control) before disease onset, and they produced high-resolution maps of linear and 3D genome organisation of their T lymphocytes.…”

Section: Do Enhancer Snps Influence the Inflammatory Response In Diabmentioning

confidence: 99%

“…The genes located in these “3D cliques” belong to the KRAB-ZFP gene family, and they found they were more commonly expressed in the immune cell population of the pancreas of human donors with T1D, suggesting the evolutionary conservation of this pathway and its relevance to disease progression. This study demonstrates that multi-enhancers containing SNPs contact at megabase resolution generate chromatin misfolding at KRAB-ZFP family genes and are associated structurally and functionally to T1D risk [ 90 ]. Study by Gao et al compared genome organisation and epigenomic profil of Th1 and Treg cells isolated from healthy and T1D participants [ 91 ].…”

Section: Do Enhancer Snps Influence the Inflammatory Response In Diabmentioning

confidence: 99%

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Diedisheim

Carcarino

Vandiedonck

et al. 2020

Molecular Metabolism

View full text Add to dashboard Cite

Background Diabetes is one of the greatest public health challenges worldwide, and we still lack complementary approaches to significantly enhance the efficacy of preventive and therapeutic approaches. Genetic and environmental factors are the culprits involved in diabetes risk. Evidence from the last decade has highlighted that deregulation in the immune and inflammatory responses increase susceptibility to type 1 and type 2 diabetes. Spatiotemporal patterns of gene expression involved in immune cell polarisation depend on genomic enhancer elements in response to inflammatory and metabolic cues. Several studies have reported that most regulatory genetic variants are located in the non-protein coding regions of the genome and particularly in enhancer regions. The progress of high-throughput technologies has permitted the characterisation of enhancer chromatin properties. These advances support the concept that genetic alteration of enhancers may influence the immune and inflammatory responses in relation to diabetes. Scope of review Results from genome-wide association studies (GWAS) combined with functional and integrative analyses have elucidated the impacts of some diabetes risk-associated variants that are involved in the regulation of the immune system. Additionally, genetic variant mapping to enhancer regions may alter enhancer status, which in turn leads to aberrant expression of inflammatory genes associated with diabetes susceptibility. The focus of this review was to provide an overview of the current indications that inflammatory processes are regulated at the genetic and epigenomic levels in diabetes, along with perspectives on future research avenues that may improve understanding of the disease. Major conclusions In this review, we provide genetic evidence in support of a deregulated immune response as a risk factor in diabetes. We also argue about the importance of enhancer regions in the regulation of immune cell polarisation and how the recent advances using genome-wide methods for enhancer identification have enabled the determination of the impact of enhancer genetic variation on diabetes onset and phenotype. This could eventually lead to better management plans and improved treatment responses in human diabetes.

show abstract

Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression

Cited by 49 publications

References 88 publications

Functional genomics in autoimmune diseases

Functional genomics in autoimmune diseases

Using functional genomics to advance the understanding of psoriatic arthritis

Regulation of inflammation in diabetes: From genetics to epigenomics evidence

Contact Info

Product

Resources

About