Histone tail mutants: versatile tools for decoding chromatin, development, and disease.

Histone modifications have been associated with transcriptional regulation, development, and disease, yet their direct functional roles remain incompletely understood due to the redundancy and promiscuity of cognate histone-modifying enzymes. Experimental strategies based on cis- or trans-acting histone mutants, including lysine-to-methionine (K-to-M) substitutions of histone H3 and other cancer-associated oncohistone variants, enable direct interrogation of individual chromatin marks and circumvent potentially confounding effects of histone-modifying enzyme knockouts. Here, we review how histone mutants have been leveraged to uncover novel principles by which chromatin pathways govern physiological, pathological, and experimental cell fate transitions and discuss the ways in which these discoveries could be exploited in the future for therapeutic benefit.