Catalytic-independent roles of chromatin modifiers in mammalian development and the implications for treating human disease.

The molecular function of chromatin modifiers is canonically assumed to be directly related to their enzymatic activities and these activities are typically measured when investigating the molecular consequences of manipulation in model systems. However, it is increasingly apparent that chromatin modifiers exhibit various functions beyond purely their enzymatic roles and, surprisingly, this is true across many classes of so-called 'writers' and 'erasers', including histone acetylases and methylases, and histone deacetylases and demethylases. Some of the most striking examples of the catalytic-independent roles of chromatin modifiers can be demonstrated in mouse models, where catalytic-inactive-encoding mutant alleles, in contrast with null alleles, can prolong survival during embryogenesis or, even more profoundly, allow otherwise embryonic lethal mutants to be born and live into adulthood. A deep understanding of the enzymatic and non-enzymatic roles of chromatin regulators is of clear relevance to understanding how they contribute to normal biology and becomes even more relevant given that many of these factors are also now therapeutic targets in the context of disease. Since therapeutic options have expanded beyond small molecule enzymatic inhibitors to include degraders and interaction blocking modalities, the time is ripe to consider these questions. In this review, we explore the catalytic-independent functions of members of four classes of chromatin modifiers, through the lens of mouse embryogenesis where much of the limited in vivo data have been reported to date. In addition, we examine how existing mouse models can be assessed to tease apart enzymatic versus non-enzymatic requirements of chromatin modifiers.