Caf1 regulates the histone methyltransferase activity of Ash1 by sensing unmodified histone H3

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Abstract

Histone modifications are one of the many key mechanisms that regulate gene expression. Ash1 is a histone H3K36 methyltransferase and is involved in gene activation. Ash1 forms a large complex with Mrg15 and Caf1/p55/Nurf55/RbAp48 (AMC complex). The Ash1 subunit alone exhibits very low activity due to the autoinhibition, and the binding of Mrg15 releases the autoinhibition. Caf1 is a scaffolding protein commonly found in several chromatin modifying complexes and has two histone binding pockets: one for H3 and the other for H4. Caf1 has the ability to sense unmodified histone H3K4 residues using the H3 binding pocket. However, the role of Caf1 in the AMC complex has not been investigated. Here, we dissected the interaction among the AMC complex subunits, revealing that Caf1 uses the histone H4 binding pocket to interact with Ash1 near the histone binding module cluster. Furthermore, we showed that H3K4 methylation inhibits AMC HMTase activity via Caf1 sensing unmodified histone H3K4 to regulate the activity in an internucleosomal manner, suggesting that crosstalk between H3K4 and H3K36 methylation. Our work revealed a delicate mechanism by which the AMC histone H3K36 methyltransferase complex is regulated.

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The online version contains supplementary material available at 10.1186/s13072-023-00487-6.

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ColabFold offers accelerated prediction of protein structures and complexes by combining the fast homology search of MMseqs2 with AlphaFold2 or RoseTTAFold. ColabFold’s 40−60-fold faster search and optimized model utilization enables prediction of close to 1,000 structures per day on a server with one graphics processing unit. Coupled with Google Colaboratory, ColabFold becomes a free and accessible platform for protein folding. ColabFold is open-source software available at https://github.com/sokrypton/ColabFold and its novel environmental databases are available at https://colabfold.mmseqs.com . ColabFold is a free and accessible platform for protein folding that provides accelerated prediction of protein structures and complexes using AlphaFold2 or RoseTTAFold.

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Regulation of chromatin by histone modifications.

Andrew Bannister, Tony Kouzarides (2011)

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

F Satterstrom, Jack A Kosmicki, Jiebiao Wang … (2020)

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

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Author and article information

Contributors

Ji-Joon Song: songj@kaist.ac.kr

Journal

Journal ID (nlm-ta): Epigenetics Chromatin

Journal ID (iso-abbrev): Epigenetics Chromatin

Title: Epigenetics & Chromatin

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8935

Publication date (Electronic): 29 April 2023

Publication date PMC-release: 29 April 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 15

Affiliations

GRID grid.37172.30, ISNI 0000 0001 2292 0500, Department of Biological Sciences, KI for BioCentury, , Korea Advanced Institute of Science and Technology (KAIST), ; Daejeon, 34141 Korea

Article

Publisher ID: 487

DOI: 10.1186/s13072-023-00487-6

PMC ID: 10148413

SO-VID: 07c25cea-6543-4bd7-bf71-7bb1430cdd1d

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Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 30 January 2023

Date accepted : 17 April 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;

Award ID: NRF-2020R1A2B5B03001517

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ScienceOpen disciplines: Genetics

Caf1 regulates the histone methyltransferase activity of Ash1 by sensing unmodified histone H3

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Most cited references 41

ColabFold: making protein folding accessible to all

Regulation of chromatin by histone modifications.

Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

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