Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [RNA-seq]

Using mouse models of several recessive and putative dominant-negative patient mutations we were able to dissect the mechanisms that underlie the recessive and dominant-negative capacities of the corresponding AIRE mutants, including a newly identified dominant-negative variant C446G We also identify an auto-regulatory mechanism by which AIRE negatively modulates its own expression. mRNA profiles of mature medullary thymic epithelial cells (mTEChi) from young (4-7 weeks old) of all mutant mice generated in the study, as well as Aire-/-,were generated by deep sequencing, using the MARSseq method.本研究借助针对数种隐性突变及疑似显性负效患者突变构建的小鼠模型，解析了对应自身免疫调节因子（AIRE, autoimmune regulator）突变体的隐性与显性负效功能的分子机制，其中包括新鉴定的显性负效变异体C446G。本研究同时鉴定出一种自身调控机制：AIRE可对其自身的基因表达产生负向调控作用。本研究采用MARSseq技术开展深度测序，获取了本研究构建的全部4~7周龄幼年突变小鼠以及Aire-/-小鼠的成熟髓质胸腺上皮细胞（mTEChi, mature medullary thymic epithelial cells）的mRNA表达谱。