Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs

Abstract

Summary: Ronin (THAP11), a DNA-binding protein that evolved from a primordial DNA transposon by molecular domestication, recognizes a hyperconserved promoter sequence to control developmentally and metabolically essential genes in pluripotent stem cells. However, it remains unclear whether Ronin or related THAP proteins perform similar functions in development. Here, we present evidence that Ronin functions within the nascent heart as it arises from the mesoderm and forms a four-chambered organ. We show that Ronin is vital for cardiogenesis during midgestation by controlling a set of critical genes. The activity of Ronin coincided with the recruitment of its cofactor, Hcf-1, and the elevation of H3K4me3 levels at specific target genes, suggesting the involvement of an epigenetic mechanism. On the strength of these findings, we propose that Ronin activity during cardiogenesis offers a template to understand how important gene programs are sustained across different cell types within a developing organ such as the heart. : Fujita et al. find that the transcriptional regulator Ronin (Thap11) appears to control embryonic heart development. Early heart-specific knockout of Ronin leads to growth defects in the developing heart and embryonic lethality, whereas slightly later Ronin loss results in severe dilated cardiomyopathy in the adult. Keywords: transcriptional control, heart development, organ growth, heart disease, dilative cardiomyopathy