Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development.
Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development.
复制标题
非编码RNA上力的转录控制手2表达和心脏发育。
DOI：
10.1038/nature20128
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发表时间：
2016-11-17
期刊：
影响因子：
64.8
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Anderson KM;Anderson DM;McAnally JR;Shelton JM;Bassel-Duby R;Olson EN
HAND2 是心脏发育的祖先调节因子，也是控制成纤维细胞重编程为心肌细胞的四种转录因子之一。小鼠中 Hand2 的缺失会导致右心室发育不全和胚胎致死。 Hand2 表达受到上游增强子的严格调控，上游增强子位于由组蛋白 H3 乙酰 Lys27 (H3K27ac) 修饰描绘的超级增强子内。在这里，我们表明，Hand2 相关的长非编码 RNA（我们将其命名为 upperhand (Uph)）的转录是通过 Hand2 增强子位点维持 RNA 聚合酶 II 的超级增强子特征和延伸所必需的。阻断 Uph 转录，但不敲低成熟转录本，会消除 Hand2 表达，导致小鼠右心室发育不全和胚胎致死。鉴于哺乳动物基因组编码的大量未表征的启动子相关长非编码RNA，Uph-Hand2调控伙伴关系提供了一种机制，通过该机制不同的非编码转录可以建立允许的染色质环境。
HAND2 is an ancestral regulator of heart development and one of four transcription factors that control the reprogramming of fibroblasts into cardiomyocytes. Deletion of Hand2 in mice results in right ventricle hypoplasia and embryonic lethality. Hand2 expression is tightly regulated by upstream enhancers that reside within a super-enhancer delineated by histone H3 acetyl Lys27 (H3K27ac) modifications. Here we show that transcription of a Hand2-associated long non-coding RNA, which we named upperhand (Uph), is required to maintain the super-enhancer signature and elongation of RNA polymerase II through the Hand2 enhancer locus. Blockade of Uph transcription, but not knockdown of the mature transcript, abolished Hand2 expression, causing right ventricular hypoplasia and embryonic lethality in mice. Given the substantial number of uncharacterized promoter-associated long non-coding RNAs encoded by the mammalian genome, the Uph–Hand2 regulatory partnership offers a mechanism by which divergent non-coding transcription can establish a permissive chromatin environment.