Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract.
Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract.
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DOI：
10.1007/s00439-015-1554-5
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发表时间：
2015-07
期刊：
影响因子：
5.3
通讯作者：
Lachke, Salil A.
中科院分区：
文献类型：
--
作者：
Agrawal, Smriti A.;Anand, Deepti;Siddam, Archana D.;Kakrana, Atul;Dash, Soma;Scheiblin, David A.;Dang, Christine A.;Terrell, Anne M.;Waters, Stephanie M.;Singh, Abhyudai;Motohashi, Hozumi;Yamamoto, Masayuki;Lachke, Salil A.
虽然大多数与早发性白内障相关的基因表现出透镜纤维细胞富集的表达，但我们对这些细胞中基因调控的理解仅限于8种转录因子的功能，并且主要是在晶状体蛋白的背景下。我们报告的小Maf转录因子Mafg和Mafk的调节几个非晶体蛋白人类白内障相关基因在纤维细胞，并建立其意义，这种疾病。我们应用了白内障基因发现的生物信息学工具iSyTE来鉴定透镜中的Mafg及其共调节子，并产生了Mafg：Mafk小鼠突变体的各种空等位基因组合用于表型和分子分析。到4个月大时，Mafg−/−：Mafk+/−突变体表现出透镜缺陷，并逐渐发展为白内障。Mafg−/−：Mafk+/−小鼠透镜的高分辨率表型表征揭示了严重紊乱的纤维细胞，而基于微阵列的表达谱鉴定了97个差异调节基因（DRG）。Mafg−/−：Mafk+/−晶状体-DRG与1）小Maf及其调控伙伴的结合基序和基因组靶标，2）iSyTE晶状体表达数据，3）String数据库中DRG之间的相互作用的综合分析，揭示了透镜中详细的小Maf调控网络，其中几个节点与白内障相关。这种方法从最初的97个DRG中识别出36个高优先级候选者。值得注意的是，8/36（22%）DRG与人类（GST 0 1、MGST 1、SC 4 MOL、UCHL 1）或小鼠（Aldh 3a 1、Crygf、Hspb 1、Pcbd 1）的白内障相关，表明包括氧化应激和甾醇合成失调在内的多因素病因。这些数据确定Mafg和Mafk为新的白内障相关候选者，并定义了它们在调节与人类白内障相关的主要非晶状体蛋白基因中的功能。
Although majority of the genes linked to early-onset cataract exhibit lens fiber cell-enriched expression, our understanding of gene regulation in these cells is limited to function of just eight transcription factors and largely in the context of crystallins. We report on small Maf transcription factors Mafg and Mafk as regulators of several non-crystallin human cataract-associated genes in fiber cells and establish their significance to this disease. We applied a bioinformatics tool for cataract gene discovery iSyTE to identify Mafg and its co-regulators in the lens, and generated various null-allelic combinations of Mafg:Mafk mouse mutants for phenotypic and molecular analysis. By age 4-months, Mafg−/−:Mafk+/− mutants exhibit lens defects that progressively develop into cataract. High-resolution phenotypic characterization of Mafg−/−:Mafk+/− mouse lens reveals severely disorganized fiber cells, while microarrays-based expression profiling identifies 97 differentially regulated genes (DRGs). Integrative analysis of Mafg−/−:Mafk+/− lens-DRGs with 1) binding-motifs and genomic targets of small Mafs and their regulatory partners, 2) iSyTE lens-expression data, and 3) interactions between DRGs in the String database, unravels a detailed small Maf regulatory network in the lens, several nodes of which are linked to cataract. This approach identifies 36 high-priority candidates from the original 97 DRGs. Significantly, 8/36 (22%) DRGs are associated with cataracts in human (GSTO1, MGST1, SC4MOL, UCHL1) or mouse (Aldh3a1, Crygf, Hspb1, Pcbd1), suggesting a multifactorial etiology that includes oxidative stress and mis-regulation of sterol synthesis. These data identify Mafg and Mafk as new cataract-associated candidates and define their function in regulating largely non-crystallin genes linked to human cataract.
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