LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.
LBH Gene Transcription Regulation by the Interplay of an Enhancer Risk Allele and DNA Methylation in Rheumatoid Arthritis.
复制标题
DOI：
10.1002/art.39746
复制
发表时间：
2016-11
影响因子：
13.3
通讯作者：
Firestein, Gary S.
中科院分区：
文献类型：
--
作者：
Hammaker, Deepa;Whitaker, John W.;Maeshima, Keisuke;Boyle, David L.;Ekwall, Anna-Karin H.;Wang, Wei;Firestein, Gary S.
To identify non-obvious therapeutic targets for rheumatoid arthritis, we performed an integrative analysis incorporating multiple ‘omics data and the ENCODE database for potential regulatory regions.该分析确定了肢体芽和心脏发育 (LBH) 基因，该基因具有与 RA/乳糜泻和狼疮相关的风险等位基因，并且可以调节 RA 中的细胞增殖。我们鉴定了一种新型 LBH 转录增强子，其具有 RA 风险等位基因 (rs906868 G (risk, Ref) /T)，位于 LBH 基因上游 6kb，具有差异甲基化位点。三个调控元件（rs906868、RA 差异甲基化位点和推定增强子）的汇合使我们研究了它们对成纤维样滑膜细胞 (FLS) LBH 调控的影响。 We cloned the 1.4kb putative enhancer with either the rs906868 Ref allele or SNP variant into reporter constructs.将构建体在体外甲基化并通过核转染转染至培养的FLS中。我们发现两种变体都增加了转录，从而证实了该区域的增强子功能。出乎意料的是，Ref 风险等位基因的转录活性显着低于 SNP 变体，并且与低 LBH 水平作为攻击性 FLS 行为的风险因素一致。使用具有纯合Ref或SNP等位基因的RA FLS系，我们证实纯合Ref系表达比SNP系更低的LBH mRNA水平。 Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status.这项研究展示了遗传学和表观遗传学之间的相互作用如何影响类风湿性关节炎中 LBH 的表达。
To identify non-obvious therapeutic targets for rheumatoid arthritis, we performed an integrative analysis incorporating multiple ‘omics data and the ENCODE database for potential regulatory regions. This analysis identified the Limb Bud and Heart development (LBH) gene, which has risk alleles associated with RA/celiac disease and lupus, and can regulate cell proliferation in RA. We identified a novel LBH transcriptional enhancer with an RA-risk allele (rs906868 G (risk, Ref) /T) 6kb upstream of the LBH gene with a differentially methylated locus. The confluence of three regulatory elements, rs906868, an RA differentially methylated locus and a putative enhancer, led us to investigate their effect on LBH regulation in fibroblast-like synoviocytes (FLS). We cloned the 1.4kb putative enhancer with either the rs906868 Ref allele or SNP variant into reporter constructs. The constructs were methylated in vitro and transfected into cultured FLS by nucleofection. We found that both variants increased transcription, thereby confirming the region’s enhancer function. Unexpectedly, the transcriptional activity of the Ref risk allele was significantly lower than the SNP variant and is consistent with low LBH levels as a risk factor for aggressive FLS behavior. Using RA FLS lines with homozygous Ref or SNP allele, we confirmed that homozygous Ref lines expressed lower LBH mRNA levels than the SNP lines. Methylation significantly reduced enhancer activity for both alleles, indicating that enhancer function is dependent on its methylation status. This study shows how the interplay between genetics and epigenetics can affect expression of LBH in rheumatoid arthritis.
登录
查看更多内容
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
5.8
作者：
Lee, Chih;Huang, Chun-Hsi
通讯作者：
Huang, Chun-Hsi
GWASdb v2：通过全基因组关联研究确定的人类遗传变异的更新数据库。
影响因子：
14.9
作者：
Li MJ;Liu Z;Wang P;Wong MP;Nelson MR;Kocher JP;Yeager M;Sham PC;Chanock SJ;Xia Z;Wang J
通讯作者：
Wang J
影响因子：
13.3
作者：
Ekwall, Anna-Karin H.;Whitaker, John W.;Hammaker, Deepa;Bugbee, William D.;Wang, Wei;Firestein, Gary S.
通讯作者：
Firestein, Gary S.
DOI：
10.1038/nrg3000
发表时间：
2011-07-12
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--