Dissecting the expression pattern during embryonic development and unveiling sustained ZGA genes with oncogenic relevance

Abstract

Zygotic genome activation (ZGA) represents a pivotal transition in early embryonic development, marking the onset of gene expression following fertilization. Despite its fundamental importance, precisely determining the timing and identifying the key genes involved in ZGA remains a significant challenge. Based on time-course patterns from RNA-seq data spanning all developmental stages, we proposed a computational framework to identify ZGA genes and the onset of ZGA across diverse species. In mice, we identified 690 ZGA-associated genes, 119 of which were previously uncharacterized. Furthermore, we defined a pivotal gene subset termed Sustained ZGA (S-ZGA) genes, which are activated from ZGA and maintain sustained expression throughout subsequent development. Epigenetic analyses revealed that promoter accessibility and H3K4me3 enrichment are primary regulatory mechanisms for S-ZGA genes. Notably, these genes exhibit strong enrichment in tumorigenesis and metastatic processes. This study establishes a computational framework that operates independently of prior knowledge to identify ZGA genes and precisely determine ZGA onset timing across diverse species, and defines a critical subset termed Sustained ZGA (S-ZGA) genes, which are potentially associated with tumorigenesis and metastatic processes. These findings provide a novel perspective on the molecular mechanisms underlying both normal development and cancer.