Anderson Kelly M, Anderson Douglas M, McAnally John R, Shelton John M, Bassel-Duby Rhonda, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature. 2016 Nov 17;539(7629):433-436. doi: 10.1038/nature20128. Epub 2016 Oct 26.
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.
HAND2是心脏发育的原始调节因子，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。在小鼠中删除Hand2会导致右心室发育不全和胚胎致死。Hand2的表达受到上游增强子的严格调控，这些增强子位于由组蛋白H3乙酰赖氨酸27（H3K27ac）修饰所界定的超级增强子内。在这里，我们表明，一种与Hand2相关的长链非编码RNA（我们将其命名为upperhand，简称Uph）的转录对于维持超级增强子特征以及RNA聚合酶II通过Hand2增强子位点的延伸是必需的。阻断Uph转录而非敲低成熟转录本，会消除Hand2的表达，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了大量未表征的启动子相关长链非编码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一个允许的染色质环境。
