Lung-specific distant enhancer cis regulates expression of FOXF1 and lncRNA FENDRR.
Lung-specific distant enhancer cis regulates expression of FOXF1 and lncRNA FENDRR.
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DOI：
10.1002/humu.24198
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发表时间：
2021-06
期刊：
影响因子：
3.9
通讯作者：
Stankiewicz P
中科院分区：
文献类型：
--
作者：
Szafranski P;Gambin T;Karolak JA;Popek E;Stankiewicz P
FOXF1基因是新生儿致命性肺发育障碍ACDMPV的致病基因，它与长链非编码RNA基因FENDRR在相反的链上相距1.7 kb，这表明它们可能是共同调控的。对位于上游286kb的FOXF1远端增强子杂合缺失的ACDMPV患者肺组织进行RNA-seq分析，发现FOXF1和FENDRR的表达分别减少了约75%和50%，并且是来自完整染色体16q24.1的单等位基因。相比之下，携带FOXF1 SNVs的ACDMPV患者双等位基因FENDRR表达降低了66-82%。确确实实，肺成纤维细胞中siRNA缺失FOXF1导致FENDRR表达降低50%。这些数据表明，肺中的FENDRR表达既受FOXF1远端增强子的顺式调节，也受FOXF1的反式调节。我们的研究结果与FENDRR参与foxf1相关疾病（包括ACDMPV）是一致的。
The FOXF1 gene, causative for a neonatal lethal lung developmental disorder ACDMPV, maps 1.7-kb away from the long noncoding RNA gene FENDRR on the opposite strand, suggesting they may be co-regulated. Using RNA-seq in lung tissue from ACDMPV patients with heterozygous deletions of the FOXF1 distant enhancer located 286-kb upstream, leaving FOXF1 and FENDRR intact, we have found that the FENDRR and FOXF1 expressions were reduced by approximately 75% and 50%, respectively, and were mono-allelic from the intact chromosome 16q24.1. In contrast, ACDMPV patients with FOXF1 SNVs had bi-allelic FENDRR expression reduced by 66–82%. Corroboratively, depletion of FOXF1 by siRNA in lung fibroblasts resulted in a 50% decrease of FENDRR expression. These data indicate that FENDRR expression in the lungs is regulated both in cis by the FOXF1 distant enhancer and in trans by FOXF1. Our findings are compatible with an involvement of FENDRR in FOXF1-related disorders, including ACDMPV.
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