A synthetic lethality screen reveals ING5 as a genetic dependency of catalytically dead Set1A/COMPASS in mouse embryonic stem cells

Significance Pluripotency and development can be governed at the level of epigenetics. Growing lines of evidence underscore the importance of the Set1A/complex of proteins associated with SET1 (COMPASS) histone 3 lysine 4 methyltransferase complex in embryogenesis and neurodevelopment. We show that the catalytic SET domain of Set1A is essential for mouse embryogenesis; however, having this domain extends the viability of embryos compared to complete loss of Set1A. We additionally show that Ing5, a core component of several complexes involved in histone acetylation, can functionally interact with Set1A ΔSET in regulating ESC viability and developmental gene expression. Insights into their physiological activity and regulation will assist our understanding of their dysfunction in disease and ultimately facilitate the discovery of new targets for future therapy.