Global discovery of lupus genetic risk variant allelic enhancer activity

Lu, Xiaoming; Xiaoting, Chen; Forney, Carmy; Donmez, Omer; Miller, Daniel; Parameswaran, Sreeja; Hong, Ted; Huang, Yongbo; Pujato, Mario; Cazares, Tareian; Miraldi, Emily R.; Ray, John J.; Boer, Carl G. de; Harley, John B.; Weirauch, Matthew T.; Kottyan, Leah C.

doi:10.1038/s41467-021-21854-5

Cited by 53 publications

(47 citation statements)

References 130 publications

(186 reference statements)

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“…Regulatory Element Locus Intersection (RELI): The RELI algorithm estimated the enrichment of specific genomic features within next generation sequencing datasets, as reported previously [21,56,57]. In addition to comparing pairs of datasets (e.g., two ChIPseq peak sets), RELI systematically estimated the significance of intersections of the genomic coordinates of genetic variants and ChIP-seq peaks, as described previously [21].…”

Section: Methodsmentioning

confidence: 99%

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

Eapen

Parameswaran

Forney

et al. 2021

Preprint

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Atopic dermatitis (AD) is one of the most common skin disorders in children. Disease etiology involves genetic and environmental factors, with the 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated epigenetic mechanisms that may account for genetic susceptibility in CD4+ T cells. To understand gene regulatory activity differences in peripheral blood T cells in AD, we measured chromatin accessibility (ATAC-seq), NFKB1 binding (ChIP-seq), and gene expression (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD and age-matched, non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of AD risk loci overlapping with AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NFκB DNA binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD-specific or Control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NFκB DNA binding motifs. Surprisingly, Control-specific NKFB1 ChIP-seq peaks were not enriched for NFKB1 motifs, instead containing motifs for other classes of human TFs, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of genotype-dependent chromatin accessibility at 36 AD risk variants (30% of AD risk loci) that could lead to genotype-dependent expression at these loci. We propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease and genotype-dependent chromatin accessibility involving NFKB binding.AUTHOR SUMMARYStimulated CD4+ T cells from patients with atopic dermatitis have disease-dependent regulation of how gene expression is regulated. This regulation is disease dependent and the way the DNA is accessible and the transcription factor NFKB1 binds is enriched for genetic risk variants. Clinically, the CD4+ T cells in the peripheral blood of patients with AD respond to stimulation in a disease and genotype-dependent manner.

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Section: Methodsmentioning

confidence: 99%

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

Eapen

Parameswaran

Forney

et al. 2021

Preprint

Self Cite

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“…Therapy with MSCs from healthy donor individuals without relation to genetic variants is increasing in prevalence in SLE. Prior studies have shown the genetic factors contributing to MSC dysfunction in SLE [ 64 – 66 ]. For instance, HLA-DM and HLA-G are identified in SLE [ 67 ] and HLA-G is associated with immunosuppressive property of MSCs [ 68 ].…”

Section: Clinical Applications Of Autologous Vs Allogeneic Mscsmentioning

confidence: 99%

Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice

Zhao

et al. 2021

Cell Biosci

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Mesenchymal stem/stromal cell (MSC)-based therapeutics is already available for treatment of a range of diseases or medical conditions. Autologous or allogeneic MSCs obtained from self or donors have their own advantages and disadvantages in their medical practice. Therapeutic benefits of using autologous vs. allogeneic MSCs are inconclusive. Transplanted MSCs within the body interact with their physical microenvironment or niche, physiologically or pathologically, and such cells in a newly established tissue microenvironment may be impacted by the pathological harmful environmental factors to alter their unique biological behaviors. Meanwhile, a temporary microenvironment/niche may be also altered by the resident or niche-surrounding MSCs. Therefore, the functional plasticity and heterogeneity of MSCs caused by different donors and subpopulations of MSCs may result in potential uncertainty in their safe and efficacious medical practice. Acknowledging a connection between MSCs’ biology and their existing microenvironment, donor-controlled clinical practice for the long-term therapeutic benefit is suggested to further consider minimizing MSCs potential harm for MSC-based individual therapies. In this review, we summarize the advantages and disadvantages of autologous vs. allogeneic MSCs in their therapeutic applications. Among other issues, we highlight the importance of better understanding of the various microenvironments that may affect the properties of niche-surrounding MSCs and discuss the clinical applications of MSCs within different contexts for treatment of different diseases including cardiomyopathy, lupus and lupus nephritis, diabetes and diabetic complications, bone and cartilage repair, cancer and tissue fibrosis.

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“…A summary of autoimmune disease risk loci used as examples in this review * Transgenic knock-out models of TNFAIP3 also discussed [24,25]. †SNP of interest identified in an MPRA targeted 91 SLE loci [41] Locus Disease(s)…”

Section: Tablementioning

confidence: 99%

Functional interrogation of autoimmune disease genetics using CRISPR/Cas9 technologies and massively parallel reporter assays

2021

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

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Global discovery of lupus genetic risk variant allelic enhancer activity

Cited by 53 publications

References 130 publications

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

Epigenetic and Transcriptional Dysregulation in CD4+ T cells of Patients with Atopic Dermatitis

Allogeneic vs. autologous mesenchymal stem/stromal cells in their medication practice

Functional interrogation of autoimmune disease genetics using CRISPR/Cas9 technologies and massively parallel reporter assays

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