CaBlCaXi: MSL2 is an allelic dosage sensor in mammals. CaBlCaXi: MSL2 is an allelic dosage sensor in mammals

Allele-specific gene expression have been observed in genomic imprinting, X chromosome inactivation, allelic exclusion of immunoglobulin loci and non-canonical random monoallelic expression. Here we show that MSL2 can regulate allele specific gene expression and we elucidate its mechanism of action. MSL2 is known to regulate gene dosage up to two fold in drosophila and mammals. In addition to its canonical role as a milder modulator, we found that the loss of MSL2 switches off gene expression completely in an allele specific way and results in biallelic to monoallelic gene expression, which will be ignored as classical down regulated genes without applying the mouse hybrid F1 system. It indicates that MSL2 can activate the expression of the allele which is otherwise inactive intrinsically. We further found this is achieved by the interplay between MSL and KANSL complex. MSL2 acts as a methylation-insensitive factor, which can prevent DNA methylation of the inactive allele, thus facilitating occupancy of methylation-sensitive factor KANSL3 and activating the gene expression. The novel mechanism of MSL2 provides a safeguarding system to warrant biallelic gene expression of intrinsically monoallelic expressed genes including X-inactivated and imprinting genes. These genes are further discovered as sex bias genes such as X-inactivation escaped genes (escapees) are expressed higher in females. Furthermore, the biallelic expression of MSL2 regulated escapees may protect females from single loss of function mutation and contribute to male severer or predominance neurodevelopmental diseases. Overall design: Allele specific differential analysis of various sequencing data from ESCs and NPCs of female and male hybrid clones.

等位基因特异性基因表达（allele-specific gene expression）已在基因组印记（genomic imprinting）、X染色体失活（X chromosome inactivation）、免疫球蛋白基因座的等位基因排斥（allelic exclusion of immunoglobulin loci）以及非经典随机单等位基因表达（non-canonical random monoallelic expression）中被观测到。本研究证实MSL2可调控等位基因特异性基因表达，并阐明了其作用机制。已知MSL2可在果蝇（Drosophila）与哺乳动物中将基因剂量上调至多两倍。除了其作为温和调控因子的经典功能外，我们发现MSL2缺失会以等位基因特异性的方式完全关闭基因表达，并使双等位基因表达（biallelic gene expression）转变为单等位基因表达（monoallelic gene expression）；若不使用小鼠杂交F1系统（mouse hybrid F1 system），这类变化会被当作经典的下调基因而被忽略。这表明MSL2可激活原本内在处于沉默状态的等位基因的表达。我们进一步发现，这一过程通过MSL复合物与KANSL复合物（KANSL complex）的相互作用实现。MSL2作为甲基化不敏感因子，可阻止沉默等位基因的DNA甲基化，从而促进甲基化敏感因子KANSL3的结合，并激活基因表达。MSL2的这一新机制为维持内在单等位基因表达基因的双等位基因表达提供了保障系统，这类基因包括X染色体失活基因与印记基因。这类基因同时被鉴定为性别偏倚基因，例如逃逸X染色体失活基因（escapees）在雌性个体中表达水平更高。此外，MSL2调控的逃逸基因的双等位基因表达，可保护雌性个体免受单功能缺失突变的影响，同时可能与男性中更严重或占比更高的神经发育疾病相关。实验设计：对雌雄杂交克隆的胚胎干细胞（embryonic stem cells, ESCs）与神经前体细胞（neural progenitor cells, NPCs）的各类测序数据进行等位基因特异性差异分析。