RBFOX2 Autoregulation Promotes Cardiomyocyte Transcriptome Maturation and Differentiation.

RBFOX2 dosage is essential for cardiomyocyte differentiation, where heterozygous cells fail to reach autoregulatory splicing thresholds, producing aberrant isoforms and reducing functional RBFOX2 below 50% of wild-type.

• Why it matters: RBFOX2 haploinsufficiency is linked to congenital heart disease, but how reduced splicing regulator dosage disrupts cardiomyocyte maturation and differentiation remained unclear.
• What they did: Human induced pluripotent stem cells with heterozygous or null RBFOX2 were differentiated into cardiomyocytes and profiled by RNA sequencing plus enhanced crosslinking and immunoprecipitation sequencing to map expression, exon usage, and RBFOX2 binding. Integrated analyses compared RBFOX2-bound targets with progressive differentiation datasets, and rescue tests used induced pluripotent stem cell-derived cardiomyocytes, engineered heart tissues, and zebrafish.
• The result: RBFOX2 drives transcriptome maturation via gene expression and alternative splicing-based isoform switching, including ACTN2; threshold-dependent autoregulatory mutually exclusive exon splicing generates early and late isoforms, and ACTN2 overexpression rescues heterozygous but not null phenotypes.

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