RNA editing is the essential function of ADAR1 and, in the absence of MDA5, is dispensable for normal adult homeostasis [RNAseq (Fetal Brain)]

Adenosine-to-Inosine (A-to-I) editing of dsRNA by ADAR proteins is a pervasive feature of the epitranscriptome. There are estimated to be over 100 million potential A-to-I editing sites in humans and A-to-I editing can have varying consequences for gene expression. Whilst editing resulting in protein recoding defines the role of ADAR2, ADAR1 has been proposed to have both editing-dependent and -independent functions. The relative contribution of these putative functions to ADAR1 biology is unclear. We demonstrate that the absence of ADAR1-mediated editing is well tolerated when the cytosolic dsRNA sensor MDA5 is deleted. These mice have normal hematopoiesis, tissue patterning and life span. A direct comparison of the complete deletion of ADAR1 and the specific loss of A-to-I editing activity demonstrates that RNA editing is the only essential function of ADAR1 in adult mice. Therefore, preventing MDA5 substrate formation by endogenous RNA is the essential in vivo function of ADAR1-mediated editing. RNAseq of Feotal Brain in a E861A point mutant of ADAR generated by deep sequencing, in duplicate, using Illumina HiSeq 2000ADAR蛋白（adenosine deaminase acting on RNA）介导的双链RNA（double-stranded RNA, dsRNA）腺苷到肌苷（A-to-I）编辑是表观转录组（epitranscriptome）中广泛存在的特征。据估计，人类体内存在超过1亿个潜在的A-to-I编辑位点，且A-to-I编辑对基因表达的调控效应具有多样性。尽管导致蛋白质重编码的编辑功能明确了ADAR2的生物学作用，但已有研究提出ADAR1同时具备依赖编辑和不依赖编辑的双重功能。目前尚不清楚这些推测的功能在ADAR1生物学过程中的相对贡献。本研究证实，当胞质双链RNA传感器MDA5（melanoma differentiation-associated protein 5）缺失时，ADAR1介导的编辑功能缺失可被良好耐受，此类小鼠的造血作用、组织模式建成及寿命均维持正常。通过直接对比完全敲除ADAR1与特异性丧失A-to-I编辑活性的小鼠模型，本研究证实RNA编辑是成年小鼠体内ADAR1唯一的必需功能。因此，通过内源性RNA阻断MDA5底物的形成，是ADAR1介导的编辑在体内的核心必需功能。本数据集采用Illumina HiSeq 2000平台，对ADAR的E861A点突变体小鼠的胎脑组织进行了双重复高通量RNA测序。