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

Area of Science:

• Developmental Biology
• Genetics
• Molecular Biology

Background:

• Gene regulatory networks are crucial for embryonic development, particularly for cardiovascular system formation.
• Long non-coding RNAs (lncRNAs) are recognized as key regulators of these genetic programs.

Purpose of the Study:

• To identify and characterize novel lncRNA loci involved in embryonic cardiovascular development.
• To investigate the function of the identified lncRNA locus Handsdown (Hdn) in heart development and its regulatory mechanisms.

Main Methods:

• Genetic inactivation of the Hdn locus in mice.
• Analysis of cardiac development in Hdn-heterozygous and homozygous mice.
• Transcriptional analysis and investigation of interactions between Hdn and its neighboring gene Hand2.

Main Results:

• The Hdn locus is essential for murine embryonic development, with haploinsufficiency leading to right ventricular hyperplasia.
• Transcriptional activity of Hdn, independent of its RNA product, suppresses the expression of the neighboring Hand2 gene.
• A switch in topologically associated domains during cardiac lineage differentiation enables Hdn to interact with Hand2 regulatory elements.

Conclusions:

• The Handsdown (Hdn) lncRNA locus is a critical regulator of cardiac development.
• Hdn functions by transcriptionally suppressing Hand2, a mechanism involving dynamic chromatin interactions.