The emerging role of epigenetics in human autoimmune disorders

Mazzone, Roberta; Zwergel, Clemens; Artico, Marco; Taurone, Samanta; Ralli, Massimo; Greco, Antonio; Mai, Antonello

doi:10.1186/s13148-019-0632-2

Cited by 236 publications

(158 citation statements)

References 162 publications

(154 reference statements)

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“…Despite the increasing number of genetic variants associated with SSc, their functional relevance is still a challenge. In addition, alongside genetic predisposition, environmental factors and epigenetic deregulation also contribute to the pathogenesis of this disease (reviewed in [68]). Our comprehensive approach has unveiled a high number of DNA methylation and expression changes in SSc CD4+ T cells compared to control (9112 DMPs, 1082 DMRs, and 3929 DEGs).…”

Section: Discussionmentioning

confidence: 99%

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Ortiz-Fernández

Andrés-León

et al. 2020

Genome Med

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Background Systemic sclerosis (SSc) is a genetically complex autoimmune disease mediated by the interplay between genetic and epigenetic factors in a multitude of immune cells, with CD4+ T lymphocytes as one of the principle drivers of pathogenesis. Methods DNA samples exacted from CD4+ T cells of 48 SSc patients and 16 healthy controls were hybridized on MethylationEPIC BeadChip array. In parallel, gene expression was interrogated by hybridizing total RNA on Clariom™ S array. Downstream bioinformatics analyses were performed to identify correlating differentially methylated CpG positions (DMPs) and differentially expressed genes (DEGs), which were then confirmed utilizing previously published promoter capture Hi-C (PCHi-C) data. Results We identified 9112 and 3929 DMPs and DEGs, respectively. These DMPs and DEGs are enriched in functional categories related to inflammation and T cell biology. Furthermore, correlation analysis identified 17,500 possible DMP-DEG interaction pairs within a window of 5 Mb, and utilizing PCHi-C data, we observed that 212 CD4+ T cell-specific pairs of DMP-DEG also formed part of three-dimensional promoter-enhancer networks, potentially involving CTCF. Finally, combining PCHi-C data with SSc GWAS data, we identified four important SSc-associated susceptibility loci, TNIP1 (rs3792783), GSDMB (rs9303277), IL12RB1 (rs2305743), and CSK (rs1378942), that could potentially interact with DMP-DEG pairs cg17239269-ANXA6, cg19458020-CCR7, cg10808810-JUND, and cg11062629-ULK3, respectively. Conclusion Our study unveils a potential link between genetic, epigenetic, and transcriptional deregulation in CD4+ T cells of SSc patients, providing a novel integrated view of molecular components driving SSc pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Ortiz-Fernández

Andrés-León

et al. 2020

Genome Med

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“…A lack of CDK6 usually leads to anemia, while overexpression leads to hematologic malignancies (Kollmann et al, 2016;Uras et al, 2017). Most of the aforementioned DMGs were enriched in cancer, T/B, NK cell differentiation, and other immune pathways, which are important for the prevention and development of disease (Kaur et al, 2013;Kuwabara et al, 2018;Mazzone et al, 2019). The differences in methylation of these genes may have an effect on immune responses in the CP.…”

Section: Dmgs Involved In Immunity and Reproductionmentioning

confidence: 99%

Whole-Genome Methylation Analysis Reveals Epigenetic Variation in Cloned and Donor Pigs

Wang

Feng

et al. 2020

Front. Genet.

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Somatic cloning has had a significant impact on the life sciences and is important in a variety of processes, including medical research and animal production. However, the application of somatic cloning has been limited due to its low success rate. Therefore, potential epigenetic variations between cloned and donor animals are still unclear. DNA methylation, one of the factors which is responsible for phenotypic differences in animals, is a commonly researched topic in epigenetic studies of mammals. To investigate the epigenetic variations between cloned and donor animals, we selected blood and ear fibroblasts of a donor pig and a cloned pig to perform whole-genome bisulfite sequencing (WGBS). A total of 215 and 707 differential methylation genes (DMGs) were identified in blood and ear fibroblasts, respectively. Functional annotation revealed that DMGs are enriched in many pathways, including T/B or natural killer (NK) cell differentiation, oocyte maturation, embryonic development, and reproductive hormone secretion. Moreover, 22 DMGs in the blood and 75 in the ear were associated with immune responses (e.g., CD244, CDK6, CD5, CD2, CD83, and CDC7). We also found that 18 DMGs in blood and 53 in ear fibroblasts were involved in reproduction. Understanding the expression patterns of DMGs, especially in relation to immune responses and reproduction, will reveal insights that will aid the advancement of future somatic cloning techniques in swine.

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“…Autoimmune Diseases? Although a correlation between HDAC-dependent epigenetic mechanisms and autoimmune disease has been explored in the literature, as described by Mazzone et al [67], iHDAC effects on B cell biology and behavior and its role as putative targets for use in autoimmune diseases have been little explored in the literature. In fact, only 35 studies published in the last 5 years approached the role for iHDACs in the modulation of B lymphocyte behavior.…”

Section: Are Ihdacs Putative Therapeutic Targets Formentioning

confidence: 99%

Epigenetic Therapy as a Putative Molecular Target to Modulate B Cell Biology and Behavior in the Context of Immunological Disorders

Costa

El-Cheikh

Carneiro

2020

Journal of Immunology Research

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Histone Deacetylase- (HDAC-) dependent epigenetic mechanisms have been widely explored in the last decade in different types of malignancies in preclinical studies. This effort led to the discovery and development of a range of new HDAC inhibitors (iHDAC) with different chemical properties and selective abilities. In fact, hematological malignancies were the first ones to have new iHDACs approved for clinical use, such as Vorinostat and Romidepsin for cutaneous T cell lymphoma and panobinostat for multiple myeloma. Besides these promising already approved iHDACs, we highlight a range of studies focusing on the HDAC-dependent epigenetic control of B cell development, behavior, and/or function. Here, we highlight 21 iHDACs which have been studied in the literature in the context of B cell development and/or dysfunction mostly focused on B cell lymphomagenesis. Regardless, we have identified 55 clinical trials using 6 out of 21 iHDACs to approach their putative roles on B cell malignancies; none of them focuses on peritoneal B cell populations. Since cells belonging to this peculiar body compartment, named B1 cells, may contribute to the development of autoimmune pathologies, such as lupus, a better understanding of the HDAC-dependent epigenetic mechanisms that control its biology and behavior might shed light on iHDAC use to manage these immunological dysfunctions. In this sense, iHDACs might emerge as a promising new approach for translational studies in this field. In this review, we discuss a putative role of iHDACs in the modulation of peritoneal B cell subpopulation’s balance as well as their role as therapeutic agents in the context of chronic diseases mediated by peritoneal B cells.

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The emerging role of epigenetics in human autoimmune disorders

Cited by 236 publications

References 162 publications

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Epigenomics and transcriptomics of systemic sclerosis CD4+ T cells reveal long-range dysregulation of key inflammatory pathways mediated by disease-associated susceptibility loci

Whole-Genome Methylation Analysis Reveals Epigenetic Variation in Cloned and Donor Pigs

Epigenetic Therapy as a Putative Molecular Target to Modulate B Cell Biology and Behavior in the Context of Immunological Disorders

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