5J9S

ENL YEATS in complex with histone H3 acetylation at K27

Summary for 5J9S

• Entry DOI: 10.2210/pdb5j9s/pdb
• Descriptor: Protein ENL, H3K27ac peptide from Histone H3.1, SULFATE ION, ... (4 entities in total)
• Functional Keywords: complex, enl yeats, histone acetyllysine, h3k27, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: Q03111 P68431
• Total number of polymer chains: 2
• Total formula weight: 21315.43

Authors

Li, Y.,Li, H. (deposition date: 2016-04-11, release date: 2017-03-08, Last modification date: 2024-10-23)

Primary citation

Wan, L.,Wen, H.,Li, Y.,Lyu, J.,Xi, Y.,Hoshii, T.,Joseph, J.K.,Wang, X.,Loh, Y.E.,Erb, M.A.,Souza, A.L.,Bradner, J.E.,Shen, L.,Li, W.,Li, H.,Allis, C.D.,Armstrong, S.A.,Shi, X.
ENL links histone acetylation to oncogenic gene expression in acute myeloid leukaemia
Nature, 543:265-269, 2017

PubMed Abstract: Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown. Here we show that the YEATS domain-containing protein ENL, but not its paralogue AF9, is required for disease maintenance in acute myeloid leukaemia. CRISPR-Cas9-mediated depletion of ENL led to anti-leukaemic effects, including increased terminal myeloid differentiation and suppression of leukaemia growth in vitro and in vivo. Biochemical and crystal structural studies and chromatin-immunoprecipitation followed by sequencing analyses revealed that ENL binds to acetylated histone H3, and co-localizes with H3K27ac and H3K9ac on the promoters of actively transcribed genes that are essential for leukaemia. Disrupting the interaction between the YEATS domain and histone acetylation via structure-based mutagenesis reduced the recruitment of RNA polymerase II to ENL-target genes, leading to the suppression of oncogenic gene expression programs. Notably, disrupting the functionality of ENL further sensitized leukaemia cells to BET inhibitors. Together, our data identify ENL as a histone acetylation reader that regulates oncogenic transcriptional programs in acute myeloid leukaemia, and suggest that displacement of ENL from chromatin may be a promising epigenetic therapy, alone or in combination with BET inhibitors, for aggressive leukaemia.

PubMed: 28241141
DOI: 10.1038/nature21687

Experimental method

X-RAY DIFFRACTION (2.702 Å)