Lamin dosage in cardiomyocytes supports nuclear organization and chromatin gating for transcription

The nuclear lamina meshwork is composed of intermediate filaments, referred to as lamins, which function to maintain nuclear integrity and organize the Lamina-Associated chromatin Domains (LADs). Studies have shown lamins support cardiomyocyte nuclear integrity, maturation, and differentiation, as well as epicardial migration. Yet, how these functions are integrated with gene expression programs and cell cycle control during heart development is unknown. We show lamin-A and -B1 are required in cardiomyocytes for perinatal mouse survival. Importantly, lamin-B1 enables cardiomyocyte maturation by maintaining LADs and chromosome territories. By examining changes in cardiomyocyte gene expression and 3D genome organization upon lamin-B1 deletion, we show lamin-B1 maintains chromatin neighborhoods, which can in turn support transcription factors to regulate genes involved in cardiomyocyte structural maturation and gradual cessation of cell division. These findings shed light on the genomic logic by which a nuclear lamina protein can collaborate with transcription factors to promote cell maturation while repressing cell cycle. Highlights1. Lamin-A/B1 dose-dependently set cardiomyocyte nuclear order and postnatal survival. 2. Lamin-B1 loss delays cardiomyocyte maturation and cell cycle exit programs. 3. Lamin-B1 shapes chromatin neighborhoods to gate maturation/cell cycle exit programs.