2021
DOI: 10.1002/art.41628
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Functional Genomic Analysis of a RUNX3 Polymorphism Associated With Ankylosing Spondylitis

Abstract: Objective. To investigate the functional consequences of the single-nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with susceptibility to ankylosing spondylitis (AS).Methods. Using nuclear extracts from Jurkat cells and primary human CD8+ T cells, the effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down assay and quantitative mass spectrometry (qMS), with validation by electrophoretic mobility shift assa… Show more

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Cited by 12 publications
(16 citation statements)
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“…We accept that recent findings highlight the fact that contact frequencies from 3C assays sometimes do not correspond to 3D proximity (Williamson et al, 2014), but taken together with the functional data presented here and other recently published findings (Vecellio et al, 2016;Vecellio et al, 2018;Vecellio et al, 2021) we are confident in our results. However, we are aware that other higher throughput techniques have been developed (eg.…”
Section: Discussionsupporting
confidence: 89%
See 1 more Smart Citation
“…We accept that recent findings highlight the fact that contact frequencies from 3C assays sometimes do not correspond to 3D proximity (Williamson et al, 2014), but taken together with the functional data presented here and other recently published findings (Vecellio et al, 2016;Vecellio et al, 2018;Vecellio et al, 2021) we are confident in our results. However, we are aware that other higher throughput techniques have been developed (eg.…”
Section: Discussionsupporting
confidence: 89%
“…It also influences many other cells, including helper T-cells, innate lymphoid, tissue resident, mucosa and gut cells (Ebihara et al, 2015;Behr et al, 2018). We have recently demonstrated that ASassociated non-coding single nucleotide polymorphisms (SNPs) in an enhancer-like region upstream of RUNX3 affect the binding of different factors: in particular the repressive nucleosome remodelling and deacetylase (NuRD) complex binds preferentially to the risk allele, while conversely interferon regulatory factor (IRF) five to the protective allele (Vecellio et al, 2021). However, the functional effects of these changes on gene transcription are still to be precisely determined.…”
Section: Introduction Backgroundmentioning
confidence: 99%
“…Here, we have demonstrated physical interaction between the distal promoter of RUNX3 and rs4648889 SNP, which we have previously functionally characterized by our group. (17, 35) Conversely, a very low interaction was observed with rs6600247 suggesting no evident functional role for this SNP in chromosome looping in this particular cellular context.…”
Section: Discussionmentioning
confidence: 84%
“…(14) It also influences many other cells, including helper T-cells, innate lymphoid, tissue resident, mucosa and gut cells (15, 16). We have recently demonstrated that AS-associated non-coding single nucleotide polymorphisms (SNPs) in an enhancer-like region upstream of RUNX3 affect the binding of different factors: in particular the repressive nucleosome remodelling and deacetylase (NuRD) complex binds preferentially to the risk allele, while conversely interferon regulatory factor (IRF) 5 to the protective allele (17). However, the functional effects of these changes on gene transcription are still to be precisely determined.…”
Section: Introductionmentioning
confidence: 99%
“…In our lab, we have so far demonstrated that the RUNX3 ASassociated SNP rs4648889 (above) mediates differential allelic binding of two regulatory factors/complexes to a putative enhancer in the region upstream of the promoter: (1) the transcription factor interferon regulatory factor (IRF) 5, which binds preferentially to the AS-protective "G" allele; and (2) components of the nucleosome remodeling and deacetylase (NuRD) complex (one of the four major ATP-dependent chromatin remodeling complexes that function as transcriptional repressors) bind preferentially instead to the AS-risk "A" allele at rs4648889 (64). Further work is necessary to confirm the functional consequences of this SNP on gene expression and the network of genes involved but preliminary experiments suggest that IRF5 knockdown in CD8+ T-cells reduces the expression of interferon gamma.…”
Section: A Strongly Associated Locus With Relationship To Immune Cellmentioning
confidence: 99%