Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression

Kumar, Vinod; Westra, Harm-Jan; Karjalainen, Juha; Zhernakova, Daria V.; Esko, Tõnu; Hrdličková, Barbara; Almeida, Rodrigo de; Zhernakova, Alexandra; Reinmaa, Eva; Võsa, Urmo; Hofker, Marten H.; Fehrmann, Rudolf S.N.; Fu, Jingyuan; Withoff, Sebo; Metspalu, Andres; Franke, Lude; Wijmenga, Cisca

doi:10.1371/journal.pgen.1003201

Cited by 258 publications

(203 citation statements)

References 32 publications

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“…In addition to a role in shaping the development of many tissues and cells, there is a defined role for lncRNAs in differentiation of T‐cell subsets 90. Evidence of the impact of long noncoding RNAs in immune function is becoming clear,91, 92 and alterations in function can be identified in autoimmune and chronic inflammation samples which are linked to lncRNAs 93. The importance of lncRNA in Treg has been elegantly demonstrated for a lncRNA (Flicr) which subtly controls the expression of FOXP3 in mouse and human Treg 94.…”

Section: Long Noncoding Rnas and Tregmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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Section: Long Noncoding Rnas and Tregmentioning

confidence: 99%

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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“…GWAS over the last decade have identified nearly 6,500 disease or trait-predisposing SNPs where only 7% of these are located in proteincoding regions of the genome [36,37] and the remaining 93% are located within non-coding areas [38,39] such as regulatory or intergenic regions. SNPs which occur in the putative regulatory region of a gene where a single base change in the DNA sequence of a potential TFBS may affect the process of gene expression are drawing more attention [40][41][42] …”

Section: Discussionmentioning

confidence: 99%

SNPs, Linkage Disequilibrium and Transcriptional Factor Binding Sites Associated with Acute Mountain Sickness among Han Chinese at the Qinghai-Tibetan Plateau

Buroker¹,

Xue²

2015

J Clin Med Genomics

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Acute mountain sickness (AMS) occurs in up to 50% of individuals ascending to high altitudes greater than 2600 meters. An AMS Han Chinese and a normal Han group were compared for 17 simple nucleotide polymorphisms (SNPs) within 9 genes that have been associated with AMS. The SNPs were analyzed with respect to linkage disequilibrium (LD) between intra-and intergenic SNP alleles and alterations in transcriptional factor binding sites (TFBS). Included in the study was the angiotensin-converting enzyme (ACE) (rs4340), the angiotensinogen (AGT) (rs699) and the angotensin II type 1 receptor (AGTR1) (rs5186) SNPs from the renin-angiotension system (RAS) as well as the GNB3 (rs2071057) SNP from G-protein signaling and a LDL apolipoprotein B (APOB) (rs693) SNP. The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) SNP and two egl nine homolog 1 (EGLN1) SNPS (rs480902 and rs516651) from the hypoxia-inducible factor (HIF) oxygen signaling pathway were included. SNPs analyzed in the vascular endothelial growth factor (VEGF) signaling pathway are the v-akt murine thymoma viral oncogene homolog 3 (AKT3) (rs4590656 and rs2291409), the endothelial cell nitric oxide synthase 3 (eNOS3) (rs1007311 and rs1799983) and the (VEGFA) (rs79469752, rs13207351, rs28357093, rs1570360 and rs3025039). These SNP alleles alter the TFBS for TF binding. Pair-wise LD was computed between SNPs. An increase in LD occurred in 32 pair-wise comparisons while a decrease was found in 22 pair-wise comparisons between the AMS and controls. Increases and decreases in LD pairs were found within and between signaling pathways and systems indicating the interaction of SNP alleles or potential TFBS from different areas of the genome. The most drastic change in TFBS occurs with ACE (I/D) SNP (rs4340) where the ACE-I allele generates 84 potential TFBS while the ACE-D allele generates only four binding sites. The alteration in TFBS generated by the 17 SNPs is discussed with respect to AMS.

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“…Genome-wide association studies (GWAS) over the last decade have identified nearly 6500 disease or trait-predisposing SNPs where only 7% of these are located in protein-coding regions of the genome [23,24] and the remaining 93% are located within non-coding areas [25,26] such as regulatory or intergenic regions. SNPs which occur in the putative regulatory region of a gene where a single base change in the DNA sequence of a potential TFBS may affect the process of gene expression are drawing more attention [7,9,27].…”

Section: Discussionmentioning

confidence: 99%

AKT3 rSNPs, Transcriptional Factor Binding Sites and Human Disease

Buroker¹

2013

OJBD

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Seven rSNPs (rs10157763, rs10927067, rs12031994, rs2125230, rs2345994, rs4132509 and rs4590646) in intron one of thev-akt murine thymoma viral oncogene homolog 3 (AKT3) gene have been significantly associated with either Chronic Mountain Sickness, Renal Cell Carcinoma risk or Aggressive Prostate Cancer. These rSNP alleles alter the DNA landscape for potential transcriptional factors (TFs) to attach, resulting in changes in transcriptional factor binding sites (TFBS). The alleles of each rSNP were found to produce unique TFBS resulting in potential changes in TF AKT3 regulation. These regulatory changes are discussed with respect to the three diseases.

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Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression

Cited by 258 publications

References 32 publications

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

SNPs, Linkage Disequilibrium and Transcriptional Factor Binding Sites Associated with Acute Mountain Sickness among Han Chinese at the Qinghai-Tibetan Plateau

AKT3 rSNPs, Transcriptional Factor Binding Sites and Human Disease

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