Embryonic stem cell factors DPPA2/4 amplify active H3K4me3-H2AK119ub chromatin domains in non-small cell lung cancer.

Abstract

Embryonic regulators are often re-expressed in cancers; however, the functional and molecular significance of this is not always understood. The epigenetic priming factors developmental pluripotency-associated 2 and 4 (DPPA2/4) have crucial roles in early development and are implicated in cancer pathogenesis. We reveal that in non-small cell lung cancer (NSCLC), DPPA2/4 coexpression is associated with poorly differentiated tumors and impaired patient outcomes. Biochemically, human DPPA2/4 multimerize for their protein stability and enhanced nucleosome binding activity. In NSCLC cells, DPPA2/4 bind CG-rich sequences including promoters of developmental genes, Wnt signaling, and catabolic genes. Chromatin state modeling revealed that DPPA2/4 preferentially bind active H3K4me3 and H3K27ac domains that were intriguingly also enriched for PRC1 and its product, H2AK119ub, which was validated by H3K4me3-H2AK119ub sequential ChIP. Knockdown experiments revealed that DPPA2/4 were required to maintain RING1B and H2AK119ub at these domains. Surprisingly, despite the presence of PRC2.1, these regions lacked any detectable H3K27me3, suggesting an uncoupling between the recruitment of PRC2 to chromatin and its catalytic product. When exogenously overexpressed in NSCLC cells where they are not normally present, DPPA2/4 bind to and promote active chromatin states, resulting in an increase in in vivo xenograft tumor growth. Our results demonstrate how, in NSCLC cells, DPPA2/4 act as molecular amplifiers of active and poised chromatin. Together, this highlights how aberrant reactivation of embryonic factors in cancers may take on new functions, promoting tumorigenesis.