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Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation

Abstract

Histone-modifying enzymes are implicated in the control of diverse DNA-templated processes including gene expression. Here, we outline historical and current thinking regarding the functions of histone modifications and their associated enzymes. One current viewpoint, based largely on correlative evidence, posits that histone modifications are instructive for transcriptional regulation and represent an epigenetic ‘code’. Recent studies have challenged this model and suggest that histone marks previously associated with active genes do not directly cause transcriptional activation. Additionally, many histone-modifying proteins possess non-catalytic functions that overshadow their enzymatic activities. Given that much remains unknown regarding the functions of these proteins, the field should be cautious in interpreting loss-of-function phenotypes and must consider both cellular and developmental context. In this Perspective, we focus on recent progress relating to the catalytic and non-catalytic functions of the Trithorax–COMPASS complexes, Polycomb repressive complexes and Clr4/Suv39 histone-modifying machineries.

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Fig. 1: Chromatin-regulator recruitment and function.
Fig. 2: Uncoupling H3K4 methylation from transcription in ESCs.
Fig. 3: Feed-forward mechanism of the PRC2 repressive machinery.
Fig. 4: The role of H3K27 modifications in gene regulation.
Fig. 5: Current technologies for interrogating the function of histone modifications.

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Acknowledgements

We thank N. Ethen for scientific illustrations and A. Piunti for critical reading and input on this manuscript. Studies in the laboratory of A.S. are supported by generous funding from the National Cancer Institute through Outstanding Investigator Award R35CA197569.

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M.M. and A.S. wrote the manuscript.

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Correspondence to Ali Shilatifard.

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Morgan, M.A.J., Shilatifard, A. Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nat Genet 52, 1271–1281 (2020). https://doi.org/10.1038/s41588-020-00736-4

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