The chromatin regulator, ZMYM2, restricts human pluripotent stem cell growth and is essential for teratoma formation

Chromatin plays fundamental roles in cellular integrity, and a growing number of chromatin proteins have been identified controlling pluripotency and early differentiation. We aimed at characterizing the role of chromatin-related genes regulating the growth and pluripotency of human embryonic stem cells (ESCs). We examined the effect of mutations in 703 genes from nearly 70 different chromatin-modifying complexes. Loss-of-function mutations in most chromatin-related genes negatively affected the survival of ESCs, and the vast majority of chromatin-associated complexes are essential for ESC growth. However, the only complexes that showed growth advantage upon their absence were the LSD-CoREST and BHC repressive complexes. Both of these complexes harbor the most potent growth restricting chromatin-related protein, Zinc finger MYM-type containing 2 (ZMYM2). Interestingly, while ZMYM2 expression is rather low at the blastocyst stage embryo its expression peaks in primed ESCs and is again down-regulated upon differentiation either in vitro or in vivo. ZMYM2-knockout ESCs over-expressed pluripotent specific genes, and showed a global increase of histone acetylation, especially at promoter regions. These cells were also refractory to differentiate in vitro, maintaining high levels of pluripotency factors when induced to differentiate. Finally, ESCs lacking ZMYM2 generally fail to produce large mature teratomas upon their injection into immunodeficient mice, and instead, generated extremely small masses comprised mostly of undifferentiated cell foci. Our results suggest a central role for ZMYM2 in the exit-from-pluripotency of ESCs, and imply that this process is essential for the transformation of human pluripotent stem cells into differentiated teratomas.