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Dev Cell. 2019 Sep 9;50(5):644-657.e8. doi: 10.1016/j.devcel.2019.07.013. Epub 2019 Aug 15.

The lncRNA Locus Handsdown Regulates Cardiac Gene Programs and Is Essential for Early Mouse Development.

Author information

1
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
2
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; Faculty of Science, Benha University, Benha 13518, Egypt.
3
Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, 61231 Bad Nauheim, Germany.
4
Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA; School of Electrical Engineering and Computer Science, Oregon State University, Corvallis, OR, USA.
5
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; German Center for Cardiovascular Regeneration (DZHK), Partner site Rhein-Main, 60590 Frankfurt am Main, Germany.
6
RNA Regulation Group, Institute of Cell Biology and Neuroscience, Goethe University, Max-von-Laue-Strasse 13, 60438 Frankfurt am Main, Germany.
7
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: grote@med.uni-frankfurt.de.

Abstract

Precisely controlled gene regulatory networks are required during embryonic development to give rise to various structures, including those of the cardiovascular system. Long non-coding RNA (lncRNA) loci are known to be important regulators of these genetic programs. We have identified a novel and essential lncRNA locus Handsdown (Hdn), active in early heart cells, and show by genetic inactivation that it is essential for murine development. Hdn displays haploinsufficiency for cardiac development as Hdn-heterozygous adult mice exhibit hyperplasia in the right ventricular wall. Transcriptional activity of the Hdn locus, independent of its RNA, suppresses its neighboring gene Hand2. We reveal a switch in a topologically associated domain in differentiation of the cardiac lineage, allowing the Hdn locus to directly interact with regulatory elements of the Hand2 locus.

KEYWORDS:

Hand2; LncRNA; TAD; cardiac development; haploinsufficiency

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