Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting.
Nucleic Acid-Sensing and Interferon-Inducible Pathways Show Differential Methylation in MZ Twins Discordant for Lupus and Overexpression in Independent Lupus Samples: Implications for Pathogenic Mechanism and Drug Targeting.
复制标题
DOI：
10.3390/genes12121898
复制
发表时间：
2021-11-26
期刊：
影响因子：
3.5
通讯作者：
Langefeld CD
中科院分区：
文献类型：
--
作者：
Marion MC;Ramos PS;Bachali P;Labonte AC;Zimmerman KD;Ainsworth HC;Heuer SE;Robl RD;Catalina MD;Kelly JA;Howard TD;Lipsky PE;Grammer AC;Langefeld CD
系统性红斑狼疮(SLE)是一种慢性、多系统、自身免疫性炎症性疾病，与基因组和非基因组因素有关。我们假设表观遗传因素是系统性红斑狼疮风险的重要贡献者，并可能为确定发病机制和治疗靶点提供信息。为了在控制遗传背景的同时验证这一假设，我们对三对欧洲血统的女性同卵双胞胎的全血基因组DNA进行了DNA甲基化分析，这对双胞胎与SLE不一致。结果在同一阵列上以四种细胞类型重复，来自一组四对不一致的丹麦女性MZ双胞胎。表观遗传学分析所涉及的基因随后在来自基因表达总集(GEO)的10个独立的SLE基因表达数据集中进行了评估。MZ双生子全血中有59个差异甲基化位点，其中包括11个新的甲基化位点。在SLE双生子中，除了两个外，所有这些基因座都是相对于未受影响的双胞胎的低甲基化。在SLE患者的多个独立数据集中，含有这些低甲基化基因的基因表达增加。无论疾病活动性、细胞类型或肾组织类型，这种模式基本上是一致的。CPGS附近的基因在SLE不一致的MZ双胞胎中表现出差异甲基化(DM)，而在独立的SLE GEO队列中表现出差异表达(DE)(DM-DE基因)，聚为两条途径：核酸感知途径和I型干扰素途径。DM-DE基因也被信息查询潜在的基因-药物相互作用，产生了41种药物的清单，其中包括一种已知的SLE疗法。DM-DE基因描述了两条重要的生物通路，这两条通路不仅反映了SLE的异质性，而且可能与不同的干扰素反应相关，这取决于个体患者的核酸分子和激活的受体的来源、类型和位置。细胞和组织的特异性分析对于了解基因因素对核酸感知和干扰素通路的失调以及这些因素是否可以成为治疗干预的合适靶点至关重要。
Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune inflammatory disease with genomic and non-genomic contributions to risk. We hypothesize that epigenetic factors are a significant contributor to SLE risk and may be informative for identifying pathogenic mechanisms and therapeutic targets. To test this hypothesis while controlling for genetic background, we performed an epigenome-wide analysis of DNA methylation in genomic DNA from whole blood in three pairs of female monozygotic (MZ) twins of European ancestry, discordant for SLE. Results were replicated on the same array in four cell types from a set of four Danish female MZ twin pairs discordant for SLE. Genes implicated by the epigenetic analyses were then evaluated in 10 independent SLE gene expression datasets from the Gene Expression Omnibus (GEO). There were 59 differentially methylated loci between unaffected and affected MZ twins in whole blood, including 11 novel loci. All but two of these loci were hypomethylated in the SLE twins relative to the unaffected twins. The genes harboring these hypomethylated loci exhibited increased expression in multiple independent datasets of SLE patients. This pattern was largely consistent regardless of disease activity, cell type, or renal tissue type. The genes proximal to CpGs exhibiting differential methylation (DM) in the SLE-discordant MZ twins and exhibiting differential expression (DE) in independent SLE GEO cohorts (DM-DE genes) clustered into two pathways: the nucleic acid-sensing pathway and the type I interferon pathway. The DM-DE genes were also informatically queried for potential gene–drug interactions, yielding a list of 41 drugs including a known SLE therapy. The DM-DE genes delineate two important biologic pathways that are not only reflective of the heterogeneity of SLE but may also correlate with distinct IFN responses that depend on the source, type, and location of nucleic acid molecules and the activated receptors in individual patients. Cell- and tissue-specific analyses will be critical to the understanding of genetic factors dysregulating the nucleic acid-sensing and IFN pathways and whether these factors could be appropriate targets for therapeutic intervention.
登录
查看更多内容
影响因子：
2.6
作者：
Grammer, A. C.;Ryals, M. M.;Lipsky, P. E.
通讯作者：
Lipsky, P. E.
影响因子：
3.2
作者：
Alaridah, Nader;Winqvist, Niclas;Godaly, Gabriela
通讯作者：
Godaly, Gabriela
DOI：
10.1002/art.39504
发表时间：
2016-04
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Alarcón-Riquelme ME;Ziegler JT;Molineros J;Howard TD;Moreno-Estrada A;Sánchez-Rodríguez E;Ainsworth HC;Ortiz-Tello P;Comeau ME;Rasmussen A;Kelly JA;Adler A;Acevedo-Vázquez EM;Cucho-Venegas JM;García-De la Torre I;Cardiel MH;Miranda P;Catoggio LJ;Maradiaga-Ceceña M;Gaffney PM;Vyse TJ;Criswell LA;Tsao BP;Sivils KL;Bae SC;James JA;Kimberly RP;Kaufman KM;Harley JB;Esquivel-Valerio JA;Moctezuma JF;García MA;Berbotto GA;Babini AM;Scherbarth H;Toloza S;Baca V;Nath SK;Aguilar Salinas C;Orozco L;Tusié-Luna T;Zidovetzki R;Pons-Estel BA;Langefeld CD;Jacob CO
通讯作者：
Jacob CO
影响因子：
12.8
作者：
Coit P;Jeffries M;Altorok N;Dozmorov MG;Koelsch KA;Wren JD;Merrill JT;McCune WJ;Sawalha AH
通讯作者：
Sawalha AH
影响因子：
3.9
作者：
Coit P;Ognenovski M;Gensterblum E;Maksimowicz-McKinnon K;Wren JD;Sawalha AH
通讯作者：
Sawalha AH