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Wednesday, February 15, 2023

David Allis (1951 - 2023) and the "histone code"

C. David Allis died on January 8, 2023. You can read about his history of awards and accomplishments in the Nature obituary with the provocative subtitle Biologist who revolutionized the chromatin and gene-expression field. This refers to his work on histone acetyltransferases (HATs) and his ideas about the histone code.

The key paper on the histone code is,

Strahl, B. D., and Allis, C. D. (2000) The language of covalent histone modifications. Nature, 403:41-45. [doi: 10.1038/47412]

Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.

They are proposing that the various modifications of histone proteins can be read as a sort of code that's recognized by other factors that bind to nucleosomes and regulation gene expression.

This is an important contribution to our understanding of the relationship between chromatin structure and gene expression. Nobody doubts that transcription is associated with an open form of chromatin that correlates with demethylation of DNA and covalent modifications of histone and nobody doubts that there are proteins that recognize modified histones. However, the key question is what comes first; the binding of transcription factors followed by changes to the DNA and histones, or do the changes to DNA and histones open the chromatin so that transcription factors can bind? These two models are referred to as the histone code model and the recruitment model.

Strahl and Allis did not address this controversy in their original paper; instead, they concentrated on what happens after histones become modified. That's what they mean by "downstream events." Unfortunately, the histone code model has been appropriated by the epigenetics cult and they do not distinguish between cause and effect. For example,

The “histone code” is a hypothesis which states that DNA transcription is largely regulated by post-translational modifications to these histone proteins. Through these mechanisms, a person’s phenotype can change without changing their underlying genetic makeup, controlling gene expression. (Shahid et al. (2022)

The language used by fans of epigenetics strongly implies that it's the modification of DNA and histones that is the primary event in regulating gene expression and not the sequence of DNA. The recruitment model states that regulation is primarily due to the binding of transcription factors to specific DNA sequences that control regulation and then lead to the epiphenomenon of DNA and histone modification.

The unauthorized expropriation of the histone code hypothesis should not be allowed to diminish the contribution of David Allis.

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