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| Status |
Public on Apr 23, 2023 |
| Title |
Structure-function relationship of ASH1L and histone H3K36 and H3K4 methylation |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
The ASH1L lysine methyltransferase plays a critical role in development and is frequently dysregulated in cancer and neurodevelopmental diseases. ASH1L catalyzes mono- and dimethylation of histone H3K36 and contains a set of uncharacterized domains. Here, we report the structure-function relationships of the C-terminal cassette of ASH1L encompassing a bromodomain (BD), a PHD finger and a bromo-associated homology (BAH) domain and show that ASH1L co-localizes with H3K4me3 but not with H3K36me2 at transcription start sites genome-wide and is involved in embryonic stem cell differentiation and transcriptional regulation of differentiation marker genes. Our crystal and NMR structural data provide mechanistic details for the recognition of H3K4me3 by PHD, the DNA binding activities of BD and BAH, and crosstalk among these domains. We show that the PHD-H3K4me3 interaction is inhibitory to the catalytic activity of ASH1L and that the DNA binding function of BAH is necessary for ASH1L engagement with the nucleosome. Our findings suggest a mechanism by which the C-terminus of ASH1L associates with chromatin and provide molecular and structural insights that are essential in therapeutic targeting of ASH1L.
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| Overall design |
ChIP-Seq of Ash1l and control in Retinoic Acid differentiated mouse ES cells
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| Contributor(s) |
Sharma R, Vann KR, Kutateladze TG |
| Citation missing |
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| |
| Submission date |
Mar 25, 2022 |
| Last update date |
Apr 25, 2023 |
| Contact name |
Rajal Sharma |
| E-mail(s) |
rajal.sharma@mssm.edu
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| Organization name |
ISMMS
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| Street address |
1425 Madison Ave., Room 16-52
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA820002 |
