Inhibition of histone H3-H4 chaperone pathways rescues C. elegans sterility by H2B loss

Oncohistone mutations are crucial drivers for tumorigenesis, but how a living organism governs the loss-of-function oncohistone remains unclear. We generated a histone H2B triple knockout (3KO) strain in Caenorhabditis elegans, which decreased the embryonic H2B, disrupted cell divisions, and caused animal sterility. By performing genetic suppressor screens, we uncovered that mutations defective in the histone H3-H4 chaperone UNC-85 restored H2B 3KO fertility by decreasing chromatin H3-H4 levels. RNA interference of other H3-H4 chaperones or H3 or H4 histones also rescued H2B 3KO sterility. We showed that blocking H3-H4 chaperones recovered cell division in C. elegans carrying the oncohistone H2B(E74K) mutation that distorts the H2B-H4 interface and induces nucleosome instability. Our results indicate that reducing chromatin H3-H4 rescues the dysfunctional H2B in vivo and suggest that inhibiting H3-H4 chaperones may provide an effective therapeutic strategy for treating cancers resulting from loss-of-function H2B oncohistone. Author summaryDysfunctional histones cause developmental defects and drive tumorigenesis. Using Caenorhabditis elegans to study histone H2B loss, we found that inhibiting histone H3-H4 chaperones restored fertility in H2B triple knockouts by decreasing chromatin H3-H4 levels. The blockade of H3-H4 chaperones recovered cell division in C. elegans carrying the oncohistone H2B(E74K) mutation that distorts the H2B-H4 interface and induces nucleosome instability. We suggest that the overall stoichiometry of histones within nucleosomes is more important than the actual abundances of histone dimers or tetramers and that inhibiting H3-H4 chaperones may provide an effective therapeutic strategy for treating cancers resulting from loss-of-function H2B oncohistone.