Transcription factor NFYa controls cardiomyocyte metabolism and proliferation during mouse fetal heart development.

Cardiomyocytes are highly metabolic cells responsible for generating the contractile force in the heart. During fetal development and regeneration, these cells actively divide but lose their proliferative activity in adulthood. The mechanisms that coordinate their metabolism and proliferation are not fully understood. Here, we study the role of the transcription factor NFYa in developing mouse hearts. Loss of NFYa alters cardiomyocyte composition, causing a decrease in immature regenerative cells and an increase in trabecular and mature cardiomyocytes, as identified by spatial and single-cell transcriptome analyses. NFYa -deleted cardiomyocytes exhibited reduced proliferation and impaired mitochondrial metabolism, leading to cardiac growth defects and embryonic death. NFYa, interacting with cofactor SP2, activates genes linking metabolism and proliferation at the transcription level. Our study identifies a nodal role of NFYa in regulating prenatal cardiac growth and a previously unrecognized transcriptional control mechanism of heart metabolism, highlighting the importance of mitochondrial metabolism during heart development and regeneration. [Display omitted] • Deleting NFYa in cardiomyocytes results in cardiac noncompaction and embryonic death • Fetal cardiomyocyte subtypes identified by multi-modal single-cell transcriptomics • NFYa deletion alters cardiomyocyte composition and mitochondrial metabolism • NFYa, working with SP2, activates metabolic gene transcription In this study, Cui et al. identified a critical role of the nuclear transcription factor Y in regulating mitochondrial metabolism and proliferation in heart muscle cells of the developing mouse heart. [ABSTRACT FROM AUTHOR]