Transcription of the Long Noncoding RNA, UpperHand, Is Required for Heart Development

The basic helix-loop-helix transcription factor HAND2 is an ancestral regulator of heart development and one of four cardiac transcription factors that controls the reprogramming of fibroblasts to cardiomyocytes. Genetic deletion of Hand2 in mice results in hypoplasia of the right ventricle and embryonic lethality. The embryonic expression of Hand2 is tightly regulated by well-characterized upstream enhancer elements, which reside within a super-enhancer delineated by H3K27ac histone modifications. Here, I show that transcription of a long noncoding RNA upstream of Hand2, which I named UpperHand (UPH), is required to maintain the H3K27ac super-enhancer signature and elongation of RNA polymerase II through the Hand2 locus. Blockade of UPH transcription by insertion of a transcription termination cassette, 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 lncRNAs encoded by the mammalian genome, the UPH-Hand2 regulatory partnership offers a mechanism by which noncoding transcription can establish a permissive chromatin environment necessary for the expression of a neighboring protein-coding gene.