scholarly journals Functional genomics in autoimmune diseases

2020 ◽  
Vol 29 (R1) ◽  
pp. R59-R65
Author(s):  
James Ding ◽  
Antonios Frantzeskos ◽  
Gisela Orozco
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Functional Genomics ◽  
Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Disease Etiology ◽  
Significant Research ◽  
Highly Correlated

Abstract 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.

scholarly journals Multi-omic Analysis of Developing Human Retina and Organoids Reveals Cell-Specific Cis-Regulatory Elements and Mechanisms of Non-Coding Genetic Disease Risk.

2021 ◽  
Author(s):  
Eric D Thomas ◽  
Andrew E Timms ◽  
Sarah Giles ◽  
Sarah Harkins-Perry ◽  
Pin Lyu ◽  
...  
Keyword(s):  
Target Genes ◽  
Disease Risk ◽  
Critical Role ◽  
Cell Types ◽  
Regulatory Elements ◽  
Human Retina ◽  
Disease States ◽  
Cell Class ◽  
Single Nucleus ◽  
Highly Correlated

Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease.

scholarly journals Application of Genetic Studies to Flow Cytometry Data and Its Impact on Therapeutic Intervention for Autoimmune Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Valeria Orrù ◽  
Maristella Steri ◽  
Francesco Cucca ◽  
Edoardo Fiorillo
Keyword(s):  
Flow Cytometry ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Immune Cell ◽  
Disease Risk ◽  
Association Studies ◽  
Large Fraction ◽  
Surface Protein ◽  
Genome Wide Association Studies ◽  
Human Immune System

In recent years, systematic genome-wide association studies of quantitative immune cell traits, represented by circulating levels of cell subtypes established by flow cytometry, have revealed numerous association signals, a large fraction of which overlap perfectly with genetic signals associated with autoimmune diseases. By identifying further overlaps with association signals influencing gene expression and cell surface protein levels, it has also been possible, in several cases, to identify causal genes and infer candidate proteins affecting immune cell traits linked to autoimmune disease risk. Overall, these results provide a more detailed picture of how genetic variation affects the human immune system and autoimmune disease risk. They also highlight druggable proteins in the pathogenesis of autoimmune diseases; predict the efficacy and side effects of existing therapies; provide new indications for use for some of them; and optimize the research and development of new, more effective and safer treatments for autoimmune diseases. Here we review the genetic-driven approach that couples systematic multi-parametric flow cytometry with high-resolution genetics and transcriptomics to identify endophenotypes of autoimmune diseases for the development of new therapies.

scholarly journals Cardiac Cell Type-Specific Gene Regulatory Programs and Disease Risk Association

2020 ◽  
Author(s):  
James D. Hocker ◽  
Olivier B. Poirion ◽  
Fugui Zhu ◽  
Justin Buchanan ◽  
Kai Zhang ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Disease Risk ◽  
Cardiovascular Disease Risk ◽  
Cell Types ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Dependent Manner ◽  
Cardiac Cell ◽  
Risk Variants ◽  
Gene Regulatory

ABSTRACTBackgroundCis-regulatory elements such as enhancers and promoters are crucial for directing gene expression in the human heart. Dysregulation of these elements can result in many cardiovascular diseases that are major leading causes of morbidity and mortality worldwide. In addition, genetic variants associated with cardiovascular disease risk are enriched within cis-regulatory elements. However, the location and activity of these cis-regulatory elements in individual cardiac cell types remains to be fully defined.MethodsWe performed single nucleus ATAC-seq and single nucleus RNA-seq to define a comprehensive catalogue of candidate cis-regulatory elements (cCREs) and gene expression patterns for the distinct cell types comprising each chamber of four non-failing human hearts. We used this catalogue to computationally deconvolute dynamic enhancers in failing hearts and to assign cardiovascular disease risk variants to cCREs in individual cardiac cell types. Finally, we applied reporter assays, genome editing and electrophysiogical measurements in in vitro differentiated human cardiomyocytes to validate the molecular mechanisms of cardiovascular disease risk variants.ResultsWe defined >287,000 candidate cis-regulatory elements (cCREs) in human hearts at single-cell resolution, which notably revealed gene regulatory programs controlling specific cell types in a cardiac region/structure-dependent manner and during heart failure. We further report enrichment of cardiovascular disease risk variants in cCREs of distinct cardiac cell types, including a strong enrichment of atrial fibrillation variants in cardiomyocyte cCREs, and reveal 38 candidate causal atrial fibrillation variants localized to cardiomyocyte cCREs. Two such risk variants residing within a cardiomyocyte-specific cCRE at the KCNH2/HERG locus resulted in reduced enhancer activity compared to the non-risk allele. Finally, we found that deletion of the cCRE containing these variants decreased KCNH2 expression and prolonged action potential repolarization in an enhancer dosage-dependent manner.ConclusionsThis comprehensive atlas of human cardiac cCREs provides the foundation for not only illuminating cell type-specific gene regulatory programs controlling human hearts during health and disease, but also interpreting genetic risk loci for a wide spectrum of cardiovascular diseases.

scholarly journals Cell-type specific cis-eQTLs in eight brain cell-types identifies novel risk genes for human brain disorders

2021 ◽  
Author(s):  
Julien Bryois ◽  
Daniela Calini ◽  
Will Macnair ◽  
Lynette Foo ◽  
Eduard Urich ◽  
...  
Keyword(s):  
Gene Expression ◽  
Disease Risk ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Specific Cell ◽  
Eqtl Analysis ◽  
Cell Type ◽  
Disease Etiology ◽  
Risk Genes ◽  
Cell Type Specific

Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogeneous brain tissues as opposed to specific cell types. To investigate the genetics of gene expression in adult human cell types from the central nervous system (CNS), we performed an eQTL analysis using single nuclei RNA-seq from 196 individuals in eight CNS cell types. We identified 6108 eGenes, a substantial fraction (43%, 2620 out of 6108) of which show cell-type specific effects, with strongest effects in microglia. Integration of CNS cell-type eQTLs with GWAS revealed novel relationships between expression and disease risk for neuropsychiatric and neurodegenerative diseases. For most GWAS loci, a single gene colocalized in a single cell type providing new clues into disease etiology. Our findings demonstrate substantial contrast in genetic regulation of gene expression among CNS cell types and reveal genetic mechanisms by which disease risk genes influence neurological disorders.

scholarly journals Single-Cell Epigenomics and Functional Fine-Mapping of Atherosclerosis GWAS Loci

2021 ◽  
Author(s):  
Tiit Örd ◽  
Kadri Õunap ◽  
Lindsey Stolze ◽  
Rédouane Aherrahrou ◽  
Valtteri Nurminen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Atherosclerotic Lesions ◽  
Genome Wide ◽  
Single Nucleus

Rationale: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation. Objective: Single nucleus chromatin accessibility profiling of the human atherosclerotic lesions was used to investigate cell type-specific patterns of CREs, to understand transcription factors establishing cell identity and to interpret CAD-relevant, non-coding genetic variation. Methods and Results: We used single nucleus ATAC-seq to generate DNA accessibility maps in > 7,000 cells derived from human atherosclerotic lesions. We identified five major lesional cell types including endothelial cells, smooth muscle cells, monocyte/macrophages, NK/T-cells and B-cells and further investigated subtype characteristics of macrophages and smooth muscle cells transitioning into fibromyocytes. We demonstrated that CAD associated genetic variants are particularly enriched in endothelial and smooth muscle cell-specific open chromatin. Using single cell co-accessibility and cis-eQTL information, we prioritized putative target genes and candidate regulatory elements for ~30% of all known CAD loci. Finally, we performed genome-wide experimental fine-mapping of the CAD GWAS variants using epigenetic QTL analysis in primary human aortic endothelial cells and STARR-Seq massively parallel reporter assay in smooth muscle cells. This analysis identified potential causal SNP(s) and the associated target gene for over 30 CAD loci. We present several examples where the chromatin accessibility and gene expression could be assigned to one cell type predicting the cell type of action for CAD loci. Conclusions: These findings highlight the potential of applying snATAC-seq to human tissues in revealing relative contributions of distinct cell types to diseases and in identifying genes likely to be influenced by non-coding GWAS variants.

scholarly journals SLE non-coding Genetic Risk Variant Determines the Epigenetic Dysfunction of an Immune Cell Specific Enhancer that Controls Disease-critical microRNA Expression

2020 ◽  
Author(s):  
Guojun Hou ◽  
Isaac T.W. Harley ◽  
Xiaoming Lu ◽  
Tian Zhou ◽  
Ning Xu ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Immune Cell ◽  
Disease Risk ◽  
Regulatory Elements ◽  
Physical Interaction ◽  
Dependent Manner ◽  
Disease Etiology ◽  
Risk Variant

AbstractThe human genome contains millions of putative regulatory elements, which regulate gene expression. We are just beginning to understand the functional consequences of genetic variation within these regulatory elements. Since the bulk of common genetic variation impacting polygenic disease phenotypes localizes to these non-coding regions of the genome, understanding the consequences will improve our understanding of the mechanisms mediating genetic risk in human disease. Here, we define the systemic lupus erythematosus (SLE) risk variant rs2431369 as likely causal for SLE and show that it is located in a functional regulatory element that modulates miR-146a expression. We use epigenomic analysis and genome-editing to show that the rs2431697-containing region is a distal enhancer that specifically regulates miR-146a expression in a cell-type dependent manner. 3D chromatin structure analysis demonstrates physical interaction between the rs2431697-containing region and the miR-146a promoter. Further, our data show that NF-kB binds the disease protective allele in a sequence-specific manner, leading to increased expression of this immunoregulatory microRNA. Our work provides a strategy for using disease-associated variants to define the functional regulatory elements of non-coding RNA molecules such as miR-146a and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.

scholarly journals Functional Inference of Gene Regulation using Single-Cell Multi-Omics

2021 ◽  
Author(s):  
Vinay K Kartha ◽  
Fabiana M Duarte ◽  
Yan Hu ◽  
Sai Ma ◽  
Jennifer G Chew ◽  
...  
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Regulatory Networks ◽  
Immunological Response ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Human Blood Cells ◽  
Functional Inference ◽  
Omic Data

Cells require coordinated control over gene expression when responding to environmental stimuli. Here, we apply scATAC-seq and scRNA-seq in resting and stimulated human blood cells. Collectively, we generate ~91,000 single-cell profiles, allowing us to probe the cis -regulatory landscape of immunological response across cell types, stimuli and time. Advancing tools to integrate multi-omic data, we develop FigR - a framework to computationally pair scATAC-seq with scRNA-seq cells, connect distal cis -regulatory elements to genes, and infer gene regulatory networks (GRNs) to identify candidate TF regulators. Utilizing these paired multi-omic data, we define Domains of Regulatory Chromatin (DORCs) of immune stimulation and find that cells alter chromatin accessibility prior to production of gene expression at time scales of minutes. Further, the construction of the stimulation GRN elucidates TF activity at disease-associated DORCs. Overall, FigR enables the elucidation of regulatory interactions across single-cell data, providing new opportunities to understand the function of cells within tissues.

scholarly journals Integrative analysis of epigenetics data identifies gene-specific regulatory elements

2019 ◽  
Author(s):  
Florian Schmidt ◽  
Alexander Marx ◽  
Marie Hebel ◽  
Martin Wegner ◽  
Nina Baumgarten ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Genome Wide ◽  
A Genome ◽  
Gene Level ◽  
Regulatory Landscape ◽  
Regulatory Sites ◽  
Validation Experiments

AbstractUnderstanding the complexity of transcriptional regulation is a major goal of computational biology. Because experimental linkage of regulatory sites to genes is challenging, computational methods considering epigenomics data have been proposed to create tissue-specific regulatory maps. However, we showed that these approaches are not well suited to account for the variations of the regulatory landscape between cell-types. To overcome these drawbacks, we developed a new method called STITCHIT, that identifies and links putative regulatory sites to genes. Within STITCHIT, we consider the chromatin accessibility signal of all samples jointly to identify regions exhibiting a signal variation related to the expression of a distinct gene. STITCHIToutperforms previous approaches in various validation experiments and was used with a genome-wide CRISPR-Cas9 screen to prioritize novel doxorubicin-resistance genes and their associated non-coding regulatory regions. We believe that our work paves the way for a more refined understanding of transcriptional regulation at the gene-level.

scholarly journals Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants

2019 ◽  
Author(s):  
Chongyuan Luo ◽  
Hanqing Liu ◽  
Fangming Xie ◽  
Ethan J. Armand ◽  
Kimberly Siletti ◽  
...  
Keyword(s):  
Single Cell ◽  
Disease Risk ◽  
Single Cells ◽  
Cortical Cell ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Integrative Approach ◽  
Risk Variants ◽  
Human Frontal Cortex ◽  
Single Nucleus

ABSTRACTSingle-cell technologies enable measure of unique cellular signatures, but are typically limited to a single modality. Computational approaches allow integration of diverse single-cell datasets, but their efficacy is difficult to validate in the absence of authentic multi-omic measurements. To comprehensively assess the molecular phenotypes of single cells in tissues, we devised single-nucleus methylCytosine, Chromatin accessibility and Transcriptome sequencing (snmC2T-seq) and applied it to post-mortem human frontal cortex tissue. We developed a computational framework to validate fine-grained cell types using multi-modal information and assessed the effectiveness of computational integration methods. Correlation analysis in individual cells revealed distinct relations between methylation and gene expression. Our integrative approach enabled joint analyses of the methylome, transcriptome, chromatin accessibility and conformation for 63 human cortical cell types. We reconstructed regulatory lineages for cortical cell populations and found specific enrichment of genetic risk for neuropsychiatric traits, enabling prediction of cell types with causal roles in disease.

scholarly journals CATaDa reveals global remodelling of chromatin accessibility during stem cell differentiation in vivo

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Gabriel N Aughey ◽  
Alicia Estacio Gomez ◽  
Jamie Thomson ◽  
Hang Yin ◽  
Tony D Southall
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Ectopic Expression ◽  
Stem Cell Differentiation ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Global Changes

During development eukaryotic gene expression is coordinated by dynamic changes in chromatin structure. Measurements of accessible chromatin are used extensively to identify genomic regulatory elements. Whilst chromatin landscapes of pluripotent stem cells are well characterised, chromatin accessibility changes in the development of somatic lineages are not well defined. Here we show that cell-specific chromatin accessibility data can be produced via ectopic expression of E. coli Dam methylase in vivo, without the requirement for cell-sorting (CATaDa). We have profiled chromatin accessibility in individual cell-types of Drosophila neural and midgut lineages. Functional cell-type-specific enhancers were identified, as well as novel motifs enriched at different stages of development. Finally, we show global changes in the accessibility of chromatin between stem-cells and their differentiated progeny. Our results demonstrate the dynamic nature of chromatin accessibility in somatic tissues during stem cell differentiation and provide a novel approach to understanding gene regulatory mechanisms underlying development.

Sign in / Sign up

Export Citation Format

Share Document