A transposable element into the human long noncoding RNA CARMEN is a switch for cardiac precursor cell specification

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• The adult heart comprises various cell types originating from multipotent precursor cells.
• Long noncoding RNAs (lncRNAs) are key regulators of cardiac lineage specification.
• The CARMEN lncRNA influences cardiomyocyte (CM) and smooth muscle cell (SMC) fate decisions through diverse isoforms.

Purpose of the Study:

• To investigate the isoform-specific functions of the CARMEN lncRNA in cardiac precursor cell (CPC) differentiation.
• To identify the role of specific CARMEN isoforms in directing cardiovascular cell fates.

Main Methods:

• Manipulation of the CARMEN locus in human primary CPCs.
• Analysis of CARMEN isoform usage during CPC differentiation.
• Identification of CARMEN-201 as a key regulator of SMC commitment.

Main Results:

• CARMEN-201 activity is linked to an alternatively spliced exon containing a MIRc short interspersed nuclear element.
• This element binds the transcriptional repressor REST (RE1 Silencing Transcription Factor).
• REST is targeted to cardiogenic loci (ISL1, IRX1, IRX5, SFRP1), inhibiting the CM gene program and inducing SMC differentiation genes.

Conclusions:

• Alternative splicing and transposable elements within lncRNAs critically regulate physiological switches in cell fate.
• The CARMEN-201 lncRNA isoform plays a vital role in SMC specification during heart development.