Positive correlation between ADAR expression and its targets suggests a complex regulation mediated by RNA editing in the human brain

A-to-I RNA editing by adenosine deaminases acting on RNA is a post-transcriptional modification that is crucial for normal life and development in vertebrates. RNA editing has been shown to be very abundant in the human transcriptome, specifically at the primate-specific Alu elements. The functional role of this wide-spread effect is still not clear; it is believed that editing of transcripts is a mechanism for their down-regulation via processes such as nuclear retention or RNA degradation. Here we combine 2 neural gene expression datasets with genome-level editing information to examine the relation between the expression of ADAR genes with the expression of their target genes. Specifically, we computed the spatial correlation across structures of post-mortem human brains between ADAR and a large set of targets that were found to be edited in their Alu repeats. Surprisingly, we found that a large fraction of the edited genes are positively correlated with ADAR, opposing the assumption that editing would reduce expression. When considering the correlations between ADAR and its targets over development, 2 gene subsets emerge, positively correlated and negatively correlated with ADAR expression. Specifically, in embryonic time points, ADAR is positively correlated with many genes related to RNA processing and regulation of gene expression. These findings imply that the suggested mechanism of regulation of expression by editing is probably not a global one; ADAR expression does not have a genome wide effect reducing the expression of editing targets. It is possible, however, that RNA editing by ADAR in non-coding regions of the gene might be a part of a more complex expression regulation mechanism.

依赖RNA的腺苷脱氨酶（adenosine deaminases acting on RNA, ADAR）介导的A-to-I RNA编辑，是脊椎动物正常生命活动与发育过程中不可或缺的转录后修饰方式。研究表明，RNA编辑在人类转录组中分布极为广泛，尤其富集于灵长类特异性Alu元件（Alu elements）中。这类广泛存在的编辑现象的生物学功能至今尚未完全阐明，学界普遍认为转录本编辑可通过核滞留或RNA降解等途径实现靶基因的表达下调。本研究将两个神经基因表达数据集与全基因组水平的编辑信息相结合，旨在探究ADAR基因表达与其靶基因表达之间的关联。具体而言，我们针对尸检人类大脑的不同脑区，计算了ADAR与一大批在其Alu重复序列中发生编辑的靶基因之间的空间相关性。令人意外的是，我们发现大部分发生编辑的基因与ADAR表达呈正相关，这与“编辑会降低靶基因表达”的既有假设相悖。在发育维度上分析ADAR与其靶基因的相关性时，可将靶基因划分为两个子集：分别与ADAR表达呈正相关与负相关。具体而言，在胚胎发育阶段，ADAR表达与大量参与RNA加工及基因表达调控的基因呈正相关。上述研究结果表明，此前提出的“通过RNA编辑实现基因表达调控”的机制可能并非普适性机制；ADAR表达并不会在全基因组范围内产生降低编辑靶基因表达的效应。不过，ADAR介导的基因非编码区RNA编辑，可能是更为复杂的基因表达调控机制的组成部分。