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 (<em>HSALNG0134318</em> in 22q11.2 and <em>HSALNG0115943</em> in 17q12) in the module most significantly enriched in known CAKUT genes (CAKUT_sig1, <em>P </em>= 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 <em>HSALNG0134318 </em>would downregulate <em>HSALNG0115943</em> 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.肾与泌尿道先天性畸形（Congenital anomalies of the kidney and urinary tract, CAKUT）是由肾脏及其流出道发育缺陷引发的一类疾病。拷贝数变异（Copy number variations, CNVs）已被证实为导致CAKUT的重要遗传变异，但绝大多数与CAKUT相关的CNVs无法归因于特定的致病基因。本研究利用人类肾脏发育转录组数据，构建了涵盖这些CNVs区域内长链非编码RNA（long noncoding RNAs, lncRNAs）的共表达网络（CNV-lncRNAs共表达网络）。结果显示，位于复发性CAKUT相关CNVs中的CNV-lncRNAs，在发育中的肾脏组织内与CAKUT相关基因的表达呈现高度相关性。我们在已知CAKUT基因显著富集的模块（CAKUT_sig1，P=1.150×10⁻⁶）中，对两个枢纽CNV-lncRNAs——22q11.2区域的*HSALNG0134318*与17q12区域的*HSALNG0115943*——的调控功能开展了实验验证。研究结果表明，CNV-lncRNAs的表达下调可使CAKUT相关基因的表达水平降低，这与我们的生物信息学分析预测结果一致。此外，敲低*HSALNG0134318*不仅会下调*HSALNG0115943*的表达，还会影响肾脏发育相关的信号通路。研究结果还显示，CAKUT_sig1模块具备多器官发育相关的功能意义。综上，本研究的发现提示CNV-lncRNAs在调控CAKUT相关基因中发挥重要作用，而在解析CAKUT相关CNVs的病因时，应将其对非编码基因组的影响纳入考量。