Functional interrogation of autoimmune disease genetics using CRISPR/Cas9 technologies and massively parallel reporter assays DOI Creative Commons
James Ding, Antonios Frantzeskos, Gisela Orozco

и другие.

Seminars in Immunopathology, Год журнала: 2021, Номер 44(1), С. 137 - 147

Опубликована: Сен. 10, 2021

Genetic studies, including genome-wide association have identified many common variants that are associated with autoimmune diseases. Strikingly, in addition to being frequently observed healthy individuals, a number of these shared across diseases diverse clinical presentations. This highlights the potential for improved disease understanding which could be achieved by characterising mechanism lead increased risk disease. Of particular interest is identifying novel drug targets or repositioning drugs currently used other The majority do not alter coding regions and it often difficult generate plausible hypothetical affect disease-relevant genes pathways. Given this area, considerable effort has been invested developing applying appropriate methodologies. Two most important technologies space include both low- high-throughput genomic perturbation using CRISPR/Cas9 system massively parallel reporter assays. In review, we introduce field functional genomics use numerous examples demonstrate recent future impact technologies.

Язык: Английский

Functional genomics in autoimmune diseases DOI Creative Commons
James Ding, Antonios Frantzeskos, Gisela Orozco

и другие.

Human Molecular Genetics, Год журнала: 2020, Номер 29(R1), С. R59 - R65

Опубликована: Май 15, 2020

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

Язык: Английский

Процитировано

12

Translating non-coding genetic associations into a better understanding of immune-mediated disease DOI Creative Commons
Christina T. Stankey, James Lee

Disease Models & Mechanisms, Год журнала: 2023, Номер 16(3)

Опубликована: Март 1, 2023

ABSTRACT Genome-wide association studies have identified hundreds of genetic loci that are associated with immune-mediated diseases. Most disease-associated variants non-coding, and a large proportion these lie within enhancers. As result, there is pressing need to understand how common variation might affect enhancer function thereby contribute (and other) In this Review, we first describe statistical experimental methods identify causal modulate gene expression, including fine-mapping massively parallel reporter assays. We then discuss approaches characterise the mechanisms by which immune function, such as clustered regularly interspaced short palindromic repeats (CRISPR)-based screens. highlight examples that, elucidating effects disease enhancers, provided important insights into uncovered key pathways disease.

Язык: Английский

Процитировано

4

A disease-associated gene desert orchestrates macrophage inflammatory responses via ETS2 DOI Creative Commons

CT Stankey,

Christophe Bourges, Tabitha Turner‐Stokes

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Май 7, 2023

Abstract Increasing global rates of autoimmune and inflammatory disease present a burgeoning threat to human health 1 . This is compounded by the limited efficacy available treatments high failure during drug development 2 – underscoring an urgent need better understand mechanisms. Here we show how genetics could address this challenge. By investigating intergenic haplotype on chr21q22, independently linked bowel (IBD), ankylosing spondylitis, primary sclerosing cholangitis Takayasu’s arteritis 3–6 , discover that causal gene, ETS2 master regulator responses in macrophages delineate risk increases expression. Genes regulated were prominently expressed affected tissues from chr21q22-associated diseases more enriched for IBD GWAS hits than almost all previously described pathways. Overexpressing resting produced activated effector state phenocopied intestinal 7 with upregulation multiple targets including TNFα IL-23. Using database cellular signatures 8 identify drugs modulate pathway validate potent anti-inflammatory activity one class small molecules vitro ex vivo Together, highlights potential common genetic associations improve both understanding treatment disease.

Язык: Английский

Процитировано

4

Approaching Shared Pathophysiology in Immune-Mediated Diseases through Functional Genomics DOI Open Access
David González‐Serna, Gonzalo Villanueva-Martín, Marialbert Acosta‐Herrera

и другие.

Genes, Год журнала: 2020, Номер 11(12), С. 1482 - 1482

Опубликована: Дек. 9, 2020

Immune-mediated diseases (IMDs) are complex pathologies that strongly influenced by environmental and genetic factors. Associations between loci susceptibility to these have been widely studied, hundreds of risk variants emerged during the last two decades, with researchers observing a shared pattern among them. Nevertheless, pathological mechanism behind associations remains challenge has just started be understood thanks functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well experimental characterization findings, constitute key elements in emerging understandings how genetics affects etiopathogenesis IMDs. In this review, we will focus on latest advances field genomics, centering our attention systemic rheumatic

Язык: Английский

Процитировано

9

Functional interrogation of autoimmune disease genetics using CRISPR/Cas9 technologies and massively parallel reporter assays DOI Creative Commons
James Ding, Antonios Frantzeskos, Gisela Orozco

и другие.

Seminars in Immunopathology, Год журнала: 2021, Номер 44(1), С. 137 - 147

Опубликована: Сен. 10, 2021

Genetic studies, including genome-wide association have identified many common variants that are associated with autoimmune diseases. Strikingly, in addition to being frequently observed healthy individuals, a number of these shared across diseases diverse clinical presentations. This highlights the potential for improved disease understanding which could be achieved by characterising mechanism lead increased risk disease. Of particular interest is identifying novel drug targets or repositioning drugs currently used other The majority do not alter coding regions and it often difficult generate plausible hypothetical affect disease-relevant genes pathways. Given this area, considerable effort has been invested developing applying appropriate methodologies. Two most important technologies space include both low- high-throughput genomic perturbation using CRISPR/Cas9 system massively parallel reporter assays. In review, we introduce field functional genomics use numerous examples demonstrate recent future impact technologies.

Язык: Английский

Процитировано

8