Acetyl-methyllysine marks chromatin at active transcription start sites
Lysine residues in histones and other proteins can be modified by post-translational modifications that encode regulatory information 1 . Lysine acetylation and methylation are especially important for regulating chromatin and gene expression 2 – 4 . Pathways involving these post-translational modif...
Saved in:
| Published in: | Nature (London) Vol. 622; no. 7981; pp. 173 - 179 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
Nature Publishing Group UK
05-10-2023
Nature Publishing Group |
| Subjects: | |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | Lysine residues in histones and other proteins can be modified by post-translational modifications that encode regulatory information
1
. Lysine acetylation and methylation are especially important for regulating chromatin and gene expression
2
–
4
. Pathways involving these post-translational modifications are targets for clinically approved therapeutics to treat human diseases. Lysine methylation and acetylation are generally assumed to be mutually exclusive at the same residue. Here we report cellular lysine residues that are both methylated and acetylated on the same side chain to form
N
ε
-acetyl-
N
ε
-methyllysine (Kacme). We show that Kacme is found on histone H4 (H4Kacme) across a range of species and across mammalian tissues. Kacme is associated with marks of active chromatin, increased transcriptional initiation and is regulated in response to biological signals. H4Kacme can be installed by enzymatic acetylation of monomethyllysine peptides and is resistant to deacetylation by some HDACs in vitro. Kacme can be bound by chromatin proteins that recognize modified lysine residues, as we demonstrate with the crystal structure of acetyllysine-binding protein BRD2 bound to a histone H4Kacme peptide. These results establish Kacme as a cellular post-translational modification with the potential to encode information distinct from methylation and acetylation alone and demonstrate that Kacme has all the hallmarks of a post-translational modification with fundamental importance to chromatin biology.
Cellular lysine residues can be both methylated and acetylated on the same sidechain to form
N
ε
-acetyl-
N
ε
-methyllysine (Kacme), which is found on histone H4 across a range of species and across mammalian tissues and is associated with active chromatin. |
|---|---|
| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Equal contributions. Author Contributions: M.D.S. conceived the project with input from W.J.L-C. W.J.L-C. made the initial discovery. Peptide synthesis, antibody development, antibody characterization, and immunoblot analyses were performed, analyzed, and interpreted by W.J.L-C., L.J.C., B.T.R., and M.D.S. Proteomic validation of Kacme in cells was performed, analyzed, and interpreted by Y.X., N.V.B., and B.A.G. Genomic distribution and sequencing experiments (ChIP, CUT&RUN, TT-TL-seq, and STL-seq) were performed, analyzed, and interpreted by W.J.L-C., L.J.C., M.M., A.P-U., J.T.Z., I.W.V., and M.D.S. In vitro enzymatic and inhibitor experiments were performed, analyzed, and interpreted by W.J.L-C., L.J.C., Y.X., B.T.R., A.P-U., B.A.G., and M.D.S. S. pombe set5Δstrains were generated by M.C.K. Structural and biophysical characterization was performed, analyzed, and interpreted by L.J.C., B.E.E., B.T.R., F.B., and M.D.S. W.J.L-C., L.J.C., and M.D.S. wrote the manuscript with input and edits from all authors. |
| ISSN: | 0028-0836 1476-4687 |
| DOI: | 10.1038/s41586-023-06565-9 |