Fig. 6.

H3.3 G34W alters enhancer landscapes by boosting the “hit-and-run” mechanism of PRC2 recruitment. A balance between the activities of K36 methyltransferases, SETD2 and NSD2, and PRC2 exists at enhancers. “Robust” enhancers have high levels of NSD2-mediated H3K36me2 while other enhancers contain low NSD2 activity. Likewise, robust enhancers have little H3K27me2/3 while low-H3K36me2 enhancers exhibit higher PRC2 activity. The H3.3 G34W oncohistone disrupts the balance by decreasing SETD2 activity and promoting spreading of PRC2-mediated H3K27 methylation at low-H3K36me2 “G34W-sensitive” enhancers. However, the high NSD2 activity at robust enhancers prevents additional PRC2 activity. As a result of the increased H3K27 methylation, H3.3 G34W decreases H3K27ac specifically at enhancers containing low NSD2 activity. H3.3 G34W suppresses enhancers associated with genes involved in the maintenance of cell identity.