Integrated analysis of copy number variation-associated lncRNAs identifies candidates contributing to the etiologies of congenital kidney anomalies

Congenital anomalies of the kidney and urinary tract (CAKUT) are disorders resulting from defects in the development of the kidneys and their outflow tract. Copy number variations (CNVs) have been identified as important genetic variations leading to CAKUT, whereas most CAKUT-associated CNVs cannot be attributed to a specific pathogenic gene. Here we construct coexpression networks involving long noncoding RNAs (lncRNAs) within these CNVs (CNV-lncRNAs) using human kidney developmental transcriptomic data. The results show that CNV-lncRNAs encompassed in recurrent CAKUT associated CNVs have highly correlated expression with CAKUT genes in the developing kidneys. The regulatory effects of two hub CNV-lncRNAs (HSALNG0134318 in 22q11.2 and HSALNG0115943 in 17q12) in the module most significantly enriched in known CAKUT genes (CAKUT_sig1, P = 1.150×10-6) are validated experimentally. Our results indicate that the reduction of CNV-lncRNAs can downregulate CAKUT genes as predicted by our computational analyses. Furthermore, knockdown of HSALNG0134318 would downregulate HSALNG0115943 and affect kidney development related pathways. The results also indicate that the CAKUT_sig1 module has function significance involving multi-organ development. Overall, our findings suggest that CNV-lncRNAs play roles in regulating CAKUT genes, and the etiologies of CAKUT-associated CNVs should take account of effects on the noncoding genome.肾与尿路先天性畸形（Congenital anomalies of the kidney and urinary tract, CAKUT）是因肾脏及其流出道发育缺陷所引发的一类疾病。拷贝数变异（Copy number variations, CNVs）已被证实是导致CAKUT的重要遗传变异，但绝大多数与CAKUT相关的CNVs无法归因于某一特定致病基因。本研究利用人类肾脏发育转录组数据，构建了这些CNVs区域内长链非编码RNA（long noncoding RNAs, lncRNAs，简称CNV-lncRNAs）的共表达网络。分析结果显示，位于复发性CAKUT相关CNVs中的CNV-lncRNAs，在发育中的肾脏内与CAKUT相关基因的表达具有高度相关性。本研究对已知CAKUT基因富集最显著的模块（CAKUT_sig1，P = 1.150×10^-6）中的两个枢纽型CNV-lncRNAs（22q11.2区域的HSALNG0134318与17q12区域的HSALNG0115943）的调控作用进行了实验验证。研究结果表明，如计算分析所预测的那样，降低CNV-lncRNAs的表达水平可下调CAKUT相关基因的表达。此外，敲低HSALNG0134318的表达还会下调HSALNG0115943的表达，并影响肾脏发育相关通路。结果还显示CAKUT_sig1模块具有多器官发育相关的功能意义。综上，本研究结果提示CNV-lncRNAs在调控CAKUT相关基因中发挥作用，而CAKUT相关CNVs的病因学研究应考虑其对非编码基因组的影响。