Fine mapping with epigenetic information and 3D structure

Orozco, Gisela

doi:10.1007/s00281-021-00906-4

Cited by 10 publications

(8 citation statements)

References 109 publications

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“…Typically, T1D co-occurs in most cases with other common organ-specific autoimmune diseases, such as autoimmune thyroiditis (predominantly), celiac disease, and gastritis (102, 103). Accordingly, Teffs isolated from nonobese diabetic (NOD) mice display a particular chromatin conformation that allows not only easier access to T1D-associated genetic loci but also access to the genes involved in other autoimmune disorders (104)(105)(106).…”

Section: Epigenetic Mechanisms Influencing Tcr Signaling and Autoimmu...mentioning

confidence: 99%

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Szukiewicz

2022

Front. Immunol.

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Endometriosis is defined as the presence of endometrial-like glands and stroma located outside the uterine cavity. This common, estrogen dependent, inflammatory condition affects up to 15% of reproductive-aged women and is a well-recognized cause of chronic pelvic pain and infertility. Despite the still unknown etiology of endometriosis, much evidence suggests the participation of epigenetic mechanisms in the disease etiopathogenesis. The main rationale is based on the fact that heritable phenotype changes that do not involve alterations in the DNA sequence are common triggers for hormonal, immunological, and inflammatory disorders, which play a key role in the formation of endometriotic foci. Epigenetic mechanisms regulating T-cell responses, including DNA methylation and posttranslational histone modifications, deserve attention because tissue-resident T lymphocytes work in concert with organ structural cells to generate appropriate immune responses and are functionally shaped by organ-specific environmental conditions. Thus, a failure to precisely regulate immune cell transcription may result in compromised immunological integrity of the organ with an increased risk of inflammatory disorders. The coexistence of endometriosis and autoimmunity is a well-known occurrence. Recent research results indicate regulatory T-cell (Treg) alterations in endometriosis, and an increased number of highly active Tregs and macrophages have been found in peritoneal fluid from women with endometriosis. Elimination of the regulatory function of T cells and an imbalance between T helper cells of the Th1 and Th2 types have been reported in the endometria of women with endometriosis-associated infertility. This review aims to present the state of the art in recognition epigenetic reprogramming of T cells as the key factor in the pathophysiology of endometriosis in the context of T-cell-related autoimmunity. The new potential therapeutic approaches based on epigenetic modulation and/or adoptive transfer of T cells will also be outlined.

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Section: Epigenetic Mechanisms Influencing Tcr Signaling and Autoimmu...mentioning

confidence: 99%

Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity

Szukiewicz

2022

Front. Immunol.

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“…It is therefore important, and non-trivial, to assign the disease-associated SNPs residing within enhancers to the genes they regulate. This can be achieved by combining evidence from a number of genomic technologies to build up evidence of the gene, and cellular context, in which the credible SNPs could act ( Delaneau et al, 2019 ; Ding et al, 2020 ; Orozco, 2022 ).…”

Section: Identifying Causal Variants Cell Type and Target Genementioning

confidence: 99%

3D genome organization links non-coding disease-associated variants to genes

Orozco

Schoenfelder

Walker

et al. 2022

Front. Cell Dev. Biol.

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Genome sequencing has revealed over 300 million genetic variations in human populations. Over 90% of variants are single nucleotide polymorphisms (SNPs), the remainder include short deletions or insertions, and small numbers of structural variants. Hundreds of thousands of these variants have been associated with specific phenotypic traits and diseases through genome wide association studies which link significant differences in variant frequencies with specific phenotypes among large groups of individuals. Only 5% of disease-associated SNPs are located in gene coding sequences, with the potential to disrupt gene expression or alter of the function of encoded proteins. The remaining 95% of disease-associated SNPs are located in non-coding DNA sequences which make up 98% of the genome. The role of non-coding, disease-associated SNPs, many of which are located at considerable distances from any gene, was at first a mystery until the discovery that gene promoters regularly interact with distal regulatory elements to control gene expression. Disease-associated SNPs are enriched at the millions of gene regulatory elements that are dispersed throughout the non-coding sequences of the genome, suggesting they function as gene regulation variants. Assigning specific regulatory elements to the genes they control is not straightforward since they can be millions of base pairs apart. In this review we describe how understanding 3D genome organization can identify specific interactions between gene promoters and distal regulatory elements and how 3D genomics can link disease-associated SNPs to their target genes. Understanding which gene or genes contribute to a specific disease is the first step in designing rational therapeutic interventions.

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“…Wang et al [12] reviews statistical methods to fine-map causal variants from GWAS findings, as well as empirical application examples in autoimmune disease genetics. Orozco et al [13] introduces fine-mapping efforts based on a set of epigenetic information including high dimensional chromatin structure in cells. Guerrini et al [14] describes a framework to utilize cap analysis of gene expression (CAGE) to reveal noncoding regulatory elements in the human genome sequences.…”

Section: Genetics and Functional Genetics Of Autoimmune Diseasesmentioning

confidence: 99%