The histone code at a crossroads: history, context, and new approaches

Recent studies have reported that catalytically dead histone-modifying enzymes can rescue the function of their null alleles. Histone 'replacement' experiments have similarly found a lack of phenotypes for some modifications. Do these findings foretell a paradigm shift for the histone code hypothesis? Here, we discuss these results through the lens of ecology, evolution, and development ('eco-evo-devo') to provide context. We then highlight recent 'top-down' approaches, which start from environmentally influenced phenotypes and then attempt to identify causal mechanisms; placing function before molecule. Using this strategy, recent work in invertebrates has found key roles for histone acetylation and small RNAs in developmental plasticity. The synthesis of traditional 'bottom-up' with new 'top-down' approaches can resolve which molecules are epiphenomenal and which are truly epigenetic.