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Nature. 2016 Nov 17;539(7629):433-436. doi: 10.1038/nature20128. Epub 2016 Oct 26.

Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

Abstract

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.

PMID:
27783597
PMCID:
PMC5261552
DOI:
10.1038/nature20128
[Indexed for MEDLINE]
Free PMC Article

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