The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2
The lncRNA Hand2os1/Uph locus orchestrates heart development through regulation of precise expression of Hand2
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DOI：
10.1242/dev.176198
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发表时间：
2019-07-01
期刊：
影响因子：
4.6
通讯作者：
Shen, Xiaohua
中科院分区：
文献类型：
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作者：
Han, Xue;Zhang, Jiejie;Shen, Xiaohua
长链非编码RNA（lncRNA）在动物体内的潜在作用和影响的探索和解剖仍然具有挑战性。在这里，使用多个敲除小鼠模型和单细胞RNA测序，我们证明了发散lncRNA Hand 2 osl/Uph对其相邻基因HAND 2的表达具有关键的复杂调节作用，随后对心脏发育和功能。小鼠中Hand 2 os 1启动子的短缺失使Hand 2 os 1转录减少至类似于8- 32%，但不能影响HAND 2表达并且不产生可辨别的心脏表型。有趣的是，小鼠中Hand 2 osl的全长缺失导致数百个心脏细胞中HAND 2的中度但普遍的上调，导致深刻的生物学后果，包括失调的心脏基因程序，先天性心脏缺陷和围产期死亡。我们提出Hand 2 osl基因座抑制HAND 2表达以抑制心肌细胞增殖，从而协调心脏细胞谱系的平衡发育。这项研究强调了lncRNA Hand 2 osl对HAND 2表达的调控复杂性，强调了需要互补的遗传和单细胞方法来描述lncRNA在动物中的功能和主要分子效应。
Exploration and dissection of potential actions and effects of long noncoding RNA (lncRNA) in animals remain challenging. Here, using multiple knockout mouse models and single cell RNA sequencing, we demonstrate that the divergent lncRNA Hand2osl/Uph has a key complex modulatory effect on the expression of its neighboring gene HAND2 and subsequently on heart development and function. Short deletion of the Hand2os1 promoter in mouse diminishes Hand2osl transcription to similar to 8-32%, but fails to affect HAND2 expression and yields no discernable heart phenotypes. Interestingly, full-length deletion of Hand2osl in mouse causes moderate yet prevalent upregulation of HAND2 in hundreds of cardiac cells, leading to profound biological consequences, including dysregulated cardiac gene programs, congenital heart defects and perinatal lethality. We propose that the Hand2osl locus dampens HAND2 expression to restrain cardiomyocyte proliferation, thereby orchestrating a balanced development of cardiac cell lineages. This study highlights the regulatory complexity of the lncRNA Hand2osl on HAND2 expression, emphasizing the need for complementary genetic and single cell approaches to delineate the function and primary molecular effects of an lncRNA in animals.