ZFP57 is a regulator of postnatal growth and life-long health

Early-life factors, including nutrition, shape long-term health outcomes. Despite the essential role of lactation in maternal nutritional support, the influence of epigenetic factors on lactation and postnatal growth remains poorly understood. Zinc-finger protein 57 (ZFP57), is an epigenetic regulator of genomic imprinting, a process that directs gene expression based on parental origin, playing a vital role in mammalian prenatal growth. Here, we identify a novel function of ZFP57 in the mammary glandI, where it serves as a key modulator of postnatal resource control, independently of imprinted genes. ZFP57 regulates multiple aspects of mammary gland functions, including ductal branching and cellular homeostasis. Its absence leads to significant differential gene expression, related to alveologenesis, lactogenesis and milk synthesis, associated with delayed lactation and altered milk composition. This results in life-long impacts on offspring including the development of metabolic syndrome. Cross-fostering reveals intricate dynamics between mother and offspring during lactation. Pups raised by a dam of a different genotype than their birth mother exhibit exacerbated metabolic features in adulthood, providing additional novel insight into the programming of offspring long-term health by maternal context. This study deepens our understanding of the interplay between epigenetic factors, lactation, and postnatal resource control.