遗传 ›› 2025, Vol. 47 ›› Issue (11): 1244-1255.doi: 10.16288/j.yczz.25-064
李轲(
), 周晓蓉, 朱东丽, 陈晓峰, 郭燕()
收稿日期:2025-02-26
修回日期:2025-05-09
出版日期:2025-11-20
发布日期:2025-05-12
通讯作者:
郭燕，博士，教授，博士生导师，研究方向：疾病遗传筛查与预防精准医疗。E-mail: guoyan253@xjtu.edu.cn作者简介:李轲，硕士研究生，专业方向：遗传学。E-mail: like77@stu.xjtu.edu.cn
基金资助:
Ke Li(), Xiaorong Zhou, Dongli Zhu, Xiaofeng Chen, Yan Guo()
Received:2025-02-26
Revised:2025-05-09
Published:2025-11-20
Online:2025-05-12
Supported by:摘要：
系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种累及多器官的自身免疫性疾病。8p23区域的FAM167A-BLK基因座是SLE既往全基因组关联研究(genome-wide association study，GWAS)报道的热点区域。为探索该区域内功能SNP(single-nucleotide polymorphism)对其相关基因BLK和FAM167A调控的作用，本研究利用GCTA软件和fnGWAS进行一系列功能注释，筛选出潜在的功能SNP，并通过双荧光素酶报告基因实验、shRNA敲低和CRISPR/dCas9敲低等功能实验进行验证。结果显示，该区域有4个功能SNP对BLK表达具有等位基因特异性增强效应，但对FAM167A无显著影响。同时，BLK可调控FAM167A表达。FAM167A可能是SLE的潜在致病基因。本研究深化了对FAM167A-BLK区域的遗传变异调控机制的理解，为解析SLE的发生机制研究提供了新视角。
李轲, 周晓蓉, 朱东丽, 陈晓峰, 郭燕. 系统性红斑狼疮易感区域FAM167A-BLK遗传变异的调控机制研究[J]. 遗传, 2025, 47(11): 1244-1255.
Ke Li, Xiaorong Zhou, Dongli Zhu, Xiaofeng Chen, Yan Guo. Exploration of the regulatory function of genetic variants at FAM167A-BLK locus in systemic lupus erythematosus[J]. Hereditas(Beijing), 2025, 47(11): 1244-1255.
表1
双荧光素酶报告基因实验所用引物序列"
| 引物名称 | 引物序列(5′→3′) |
|---|---|
| BLK promoter扩增引物 | 上游：CCGCTCGAGCACCTCTCTTCCGCCTTTCT(Xho I) |
| 下游：CCCAAGCTTGTTTTCATGGCTTGTGGCTT(Hind III) | |
| FAM167A promoter扩增引物 | 上游：CCGCTCGAGGAAGATCTGGATCAAGGCTGTGAC(Xho I) |
| 下游：CCCAAGCTTGCTGCTCCTTTCGGAAAGGACTTT(Hind III) | |
| rs2736337片段扩增引物 | 上游：CGGGGTACCTGGAGCAATGCCTGTCATCA(Kpn I) |
| 下游：CCGCTCGAGTGCACATCTCGAAATTCTGTGG(Xho I) | |
| rs2736337(C)突变引物 | 上游：TTGTCTTACCGTTCTGGAGGCTGGAAGTCCAA |
| 下游：CCAGAACGGTAAGACAATAAACTTCTATTGTTTAAGCCAC | |
| rs2736340片段扩增引物 | 上游：CGGGGTACCCCACCCCTGTTCACCCATAA(Kpn I) |
| 下游：CCGCTCGAGTTACCCTTGCCTTGTGCCTT(Xho I) | |
| rs2736340(C)突变引物 | 上游：TGTACCCACCAATCAGACCCATCACTAATGGTG |
| 下游：TCTGATTGGTGGGTACATATACAATGCGATGG | |
| rs9693589片段扩增引物 | 上游：CGACGCGTCCCCCATCCCAGACCAAATC(Mlu I) |
| 下游：CCGCTCGAGTCAAGGCGGGACTGAGACTA(Xho I) | |
| rs9693589(G)突变引物 | 上游：TCAAGTGATCTGCCCCGCCCTCAGCCTCCCAAAGTG |
| 下游：CGGGGCAGATCACTTGAGGTCAGGAGTTCGAG | |
| rs2618476片段扩增引物 | 上游：CGGGGTACCATGAATGGATCGCTGCCTCA(Kpn I) |
| 下游：CCGCTCGAGTTACTGCAAACGCACAATTCCT(Xho I) | |
| rs2618476(T)突变引物 | 上游：GGCAAATGACTGTTGCTTTCGTTTTATTTGTTTGTTTCTGAATG |
| 下游：AGCAACAGTCATTTGCCTTGAGCCAGATGCTC |
表2
qRT-PCR实验所用引物序列"
| qRT-PCR靶向基因 | 引物序列(5′→3′) |
|---|---|
| BLK | 上游：GGATGGGGCTGGTAAGTAGC |
| 下游：CATCCAGGTGTTCATCGGGC | |
| FAM167A | 上游：AAGGAACTGACGGAGATGCG |
| 下游：GCTCGTAGGTGGCATCGTT | |
| PRDM1 | 上游：GCAACTGGATGCGCTATGTG |
| 下游：GCAGGGATGGGCTTAATGGT | |
| ETS1 | 上游：ATGAATGGAGCAGCCCTCTG |
| 下游：CGGGATTCTGGATAGGCTGG | |
| LYN | 上游：TGTGAGAGATCCAACGTCCA |
| 下游：GGTGGATGCCATCATAGGGG | |
| BANK1 | 上游：CAGCGCCCCCAGGAAATAC |
| 下游：CAGCAACTCCAAATGCCGAA | |
| IRF5 | 上游：GGGCTTCAATGGGTCAACG |
| 下游：GCCTTCGGTGTATTTCCCTG | |
| IL-6 | 上游：TTCGGTCCAGTTGCCTTCTC |
| 下游：CTGAGATGCCGTCGAGGATG | |
| STAT4 | 上游：GAGACCAGCTCATTGCCTGT |
| 下游：CAATGTGGCAGGTGGAGGAT |
表3
CRISPR/dCas9敲低实验所用引物序列"
| 引物名称 | 引物序列(5′→3′) |
|---|---|
| BLK_dCas9-1- sgRNA1 | 上游：ACCGACCAGTGAGGCTGAAAGAA |
| 下游：TAACTTCTTTCAGCCTCACTGGT | |
| BLK_dCas9-1- sgRNA2 | 上游：ACCGTTGCTAACTCTGCCGGACT |
| 下游：TAACAGTCCGGCAGAGTTAGCAA | |
| BLK_dCas9-2- sgRNA1 | 上游：ACCGCTGCCCTGGTGCACACAGA |
| 下游：TAACTCTGTGTGCACCAGGGCAG | |
| BLK_dCas9-2- sgRNA2 | 上游：ACCGGCTGTTAAACCAAAACCCC |
| 下游：TAACGGGGTTTTGGTTTAACAGC | |
| FAM167A_dCas9-1- sgRNA1 | 上游：ACCGCCGGAAGGTGGGTTCGCGC |
| 下游：TAACGCGCGAACCCACCTTCCGG | |
| FAM167A_dCas9-1- sgRNA2 | 上游：ACCGGGCGCTGCTCCTTTCGGAA |
| 下游：TAACTTCCGAAAGGAGCAGCGCC | |
| FAM167A_dCas9-2- sgRNA1 | 上游：ACCGGAGGAGGCGGCGGGGACAC |
| 下游：TAACGTGTCCCCGCCGCCTCCTC | |
| FAM167A_dCas9-2- sgRNA2 | 上游：ACCGAACCGCCCTGACGCAACGC |
| 下游：TAACGCGTTGCGTCAGGGCGGTT |
图1
将4个SNP优先排序为FAM167A-BLK基因座的潜在功能变异位点 从FAM167A-BLK基因座筛选潜在功能性SNP。条件分析结果筛选出一个独立关联的SNP(P<5×10-8)。通过LD分析(r2>0.8)结合fnGWAS分析获得了4个候选SNP。该位点图由LocusZoom[16]生成。表观遗传注释通过WashU EpiGenome浏览器可视化呈现。"
表4
利用fnGWAS网站对筛选的4个潜在功能性SNP的注释结果"
| SNP | 位置 | 基因 | JASPAR_ CORE_2018 | HOCO MOCOv11 | Transfac | Swiss Regulon | Jolma 2013 |
|---|---|---|---|---|---|---|---|
| rs2736337 (C/T) | 基因间区 | BLK、FAM167A | SMAD3(C) | SMAD4(C)、TBX2(C) | HNF1A(T) | HNF1A(T) | − |
| rs2736340 (T/C) | 基因间区 | BLK | NFYA(C)、NFYB(C)、RREB1(C) | NFYA(C)、NFYB(C)、NFYC(C)、RREB1(C)、EVX1(T)、HOXA1(T)、HOXA5(T) | NFYA(C)、NFYC(C) | RREB1(C) | − |
| rs9693589 (A/G) | 基因间区 | BLK、FAM167A | SP4(G)、E2F3(G)、E2F4(G) | E2F1(G)、 E2F3(G)、 E2F4(G)、SALL4(A)、 SPIC(A) | SP4(G)、E2F3(G)、E2F4(G)、MAZ(G)、KLF1(A)、KLF13(A) | MAZ(G) | SP4(G) |
| rs2618476 (C/T) | 内含子区 | BLK、FAM167A | IRF7(T)、IRF9(T)、IRF1(T) | IRF7(T)、IRF2(T)、 IRF1(T) | IRF7(T)、IRF9(T)、IRF5(T)、IRF2(T)、RFX1(C)、 ZNF350(C) | − | IRF7(T)、IRF9(T)、IRF5(T) |
图2
双荧光素酶报告基因检测SNP对BLK启动子活性的调控效应 在HEK293T细胞中，以BLK promoter-Luc+的荧光信号值作为基准对照，检测携带SNP rs2736337(A)、rs2736340(B)、rs9693589(C)和rs2618476(D)片段的SNP-BLK promoter-Luc+质粒的荧光素酶活性。荧光素酶活性通过共转染的Renilla信号进行标准化。数据以均值±标准差表示。*P<0.05，**P<0.01，***P<0.001(n≥3)。"
图3
双荧光素酶报告基因检测SNP对FAM167A启动子活性的调控效应 在HEK293T细胞中，以FAM167A promoter-Luc+的荧光信号值作为基准对照，检测携带SNP rs2736337(A)、rs2736340(B)、rs9693589(C)和rs2618476(D)片段的SNP-FAM167A promoter-Luc+质粒的荧光素酶活性。荧光素酶活性通过共转染的Renilla信号进行标准化。数据以均值±标准差表示。*P<0.05，**P<0.01，***P<0.001(n≥3)。"
图4
FAM167A基因可能受到BLK的调控 A和B：在Raji细胞中BLK敲低对FAM167A表达的影响。C和D：在Raji细胞中FAM167A敲低对BLK表达的影响。shRNA敲低组(A和C)，每组使用了两个shRNA质粒(shRNA-1和shRNA-2)和shRNA-NC质粒(阴性对照)；CRISPR/dCas9敲低组(B和D)，每组使用两个dCas9质粒(dCas9-1、dCas9-2)和空载lentiCRISPRv2质粒(NC)。数据以均值±标准差表示。*P<0.05，**P<0.01，***P<0.001 (n≥3)。"
图5
FAM167A基因影响免疫相关标记基因和通路下游基因的表达 A：FAM167A通过shRNA敲低对Raji细胞中不同免疫标志基因表达的影响。shRNA敲低组，使用两个shRNA质粒(shRNA-1和shRNA-2)和shRNA-NC质粒(阴性对照)；B：FAM167A通过CRISPR/dCas9-KRAB敲低对Raji细胞中不同免疫标志基因表达的影响。使用两个dCas9质粒(dCas9-1、dCas9-2)和空载lentiCRISPRv2质粒(NC)。数据以均值±标准差表示。*P<0.05，**P<0.01，***P<0.001(n≥3)。"
图6
FAM167A-BLK基因座区域易感位点与SLE之间的潜在调控模型 FAM167A-BLK基因座区域的4个功能性SNP影响BLK的表达，而BLK调控FAM167A的表达，进而可能增加SLE的患病风险。"
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