title: Transcription of the non-coding RNA upperhand controls Hand2 expression and heart development.
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.
authors: 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.
authors: Kelly M
authors: KM
authors: Anderson
authors: 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.
authors: Douglas M
authors: DM
authors: Anderson
authors: 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.
authors: John R
authors: JR
authors: McAnally
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: John M
authors: JM
authors: Shelton
authors: 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.
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: 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.
authors: Eric N
authors: EN
authors: Olson
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D020964:Embryo Loss / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D055786:Gene Knockout Techniques; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics; D006352:Heart Ventricles / Q000002:abnormalities; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012319:RNA Polymerase II / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D061805:Transcription Elongation, Genetic; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D012319:RNA Polymerase II; D062085:RNA, Long Noncoding; C498766:Hand2 protein, mouse