8I60

Crystal structure of GAS41 YEATS domain in complex with histone H3K27cr

Summary for 8I60

• Entry DOI: 10.2210/pdb8i60/pdb
• Descriptor: YEATS domain-containing protein 4, ALA-ARG-KCR-SER-ALA-PRO, SULFATE ION, ... (5 entities in total)
• Functional Keywords: histone h3 lysine crotonylation, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 35746.81

Authors

Konuma, T.,Zhou, M.-M. (deposition date: 2023-01-26, release date: 2023-07-26)

Primary citation

Liu, N.,Konuma, T.,Sharma, R.,Wang, D.,Zhao, N.,Cao, L.,Ju, Y.,Liu, D.,Wang, S.,Bosch, A.,Sun, Y.,Zhang, S.,Ji, D.,Nagatoishi, S.,Suzuki, N.,Kikuchi, M.,Wakamori, M.,Zhao, C.,Ren, C.,Zhou, T.J.,Xu, Y.,Meslamani, J.,Fu, S.,Umehara, T.,Tsumoto, K.,Akashi, S.,Zeng, L.,Roeder, R.G.,Walsh, M.J.,Zhang, Q.,Zhou, M.M.
Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.
Mol.Cell, 83:2206-2221.e11, 2023

PubMed Abstract: Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

PubMed: 37311463
DOI: 10.1016/j.molcel.2023.05.022

Experimental method

X-RAY DIFFRACTION (2.3 Å)