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Understanding the language of Lys36 methylation at histone H3

Key Points

  • Methylation of Lys36 on histone H3 (H3K36) is an important modification for multiple cellular processes. To date, at least eight enzymes have been reported to methylate H3K36, and these can be broadly defined into two groups: mono- and dimethylases, and trimethylases.

  • Although some reports have described H3K36 methylation in transcriptional repression, a large body of data has implicated this modification in transcriptional activation. However, this modification appears to be used in both initiation and elongation.

  • Recent reports have shown that H3K36 methylation and nucleosome positioning are important in alternative splicing. H3K36 methylation has also been reported to function in DNA replication, recombination and repair.

  • Perturbations in the enzymes that maintain the levels of H3K36 methylation have been reported in numerous diseases, such as Sotos syndrome, Wolf–Hirschhorn syndrome, acute myeloid leukaemia, multiple myeloma and prostate cancer.

Abstract

Histone side chains are post-translationally modified at multiple sites, including at Lys36 on histone H3 (H3K36). Several enzymes from yeast and humans, including the methyltransferases SET domain-containing 2 (Set2) and nuclear receptor SET domain-containing 1 (NSD1), respectively, alter the methylation status of H3K36, and significant progress has been made in understanding how they affect chromatin structure and function. Although H3K36 methylation is most commonly associated with the transcription of active euchromatin, it has also been implicated in diverse processes, including alternative splicing, dosage compensation and transcriptional repression, as well as DNA repair and recombination. Disrupted placement of methylated H3K36 within the chromatin landscape can lead to a range of human diseases, underscoring the importance of this modification.

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Figure 1: Domain structures of enzymes that methylate H3K36.
Figure 2: H3K36me3-dependent prevention of aberrant transcription in yeast.
Figure 3: H3K36me3 influences alternative splicing in a cell-type specific manner.
Figure 4: Model for H3K36 methylation at sites of DNA damage.
Figure 5: NSD proteins can act as oncoproteins.

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Acknowledgements

We apologize to those researchers whose work could not be cited owing to space constraints. We thank B. Martinez and K. Eterovic for assistance with the figures, as well as S. Ercan, P. Masamha and A. Sataluri for critical comments regarding the manuscript. Work in the laboratory of P.B.C. has been supported in part by the Robert A. Welch Foundation (AU-1569). Work in the laboratory of E.J.W. is supported by the US National Institutes of Health (5R00GM080447).

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Glossary

Dosage compensation

The mechanism by which expression levels from sex chromosomes are adjusted. In mammalian systems, one copy of the X chromosome is silenced in the female. By contrast, in Drosophila, genes on the male X chromosome are expressed at twofold levels.

SET domain

(Suppressor of variegation 3-9, Enhancer of Zeste and Trithorax domain). A catalytic domain that uses S-adenosylmethionine to transfer methyl groups to substrates.

PWWP domain

(Pro-Trp-Trp-Pro domain). A chromatin-interacting domain that has recently been shown to bind trimethylated Lys36 on histone H3.

Plant homeodomain fingers

(PHD fingers). Motifs that bind zinc and have been shown to bind methylated residues.

Allosteric

Pertaining to the process by which a binding event at one site influences the activity of an enzyme or protein at a second, distant site. This may lead to activation or inhibition by cooperation between ligands, when a ligand bound at one site affects the affinity of another site for its ligand by inducing transitions between distinct conformational states.

Heterogeneous nuclear ribonucleoprotein L

(hnRNPL). A member of a highly abundant family of RNA-binding proteins known to associate with newly synthesized pre-mRNA.

Pro isomerization

Peptide bonds to Pro residues can exist in either a cis or a trans state, and the transitions can be catalysed by prolyl isomerase enzymes.

Anti-silencing function 1

(Asf1). A histone chaperone protein that associates with newly synthesized histones and is involved in chromatin synthesis.

Reader protein

A protein that recognizes and binds post-translational modifications on histones.

Chromodomain

A domain of 50 residues that has been shown to bind methylated residues.

Polypyrimidine tract-binding protein

(PTB). A protein that has been implicated as an antagonist of exon definition, the action of which results in the repression of exon inclusion.

Fibroblast growth factor receptor 2

(FGFR2). A membrane-bound receptor that undergoes alternative splicing and is subject to regulation by methylation of Lys36 on histone H3.

Epithelial splicing regulatory protein

(ESRP). An alternative splicing factor that is enriched in epithelial tissues and is responsible for enforcing specific exon inclusion.

Non-homologous end joining

(NHEJ). The main pathway that is used primarily in the G1 phase of the cell cycle to repair chromosomal DNA double-strand breaks in somatic cells. In contrast to homologous-recombination repair, NHEJ is error-prone because it leads to the joining of heterologous ends.

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Wagner, E., Carpenter, P. Understanding the language of Lys36 methylation at histone H3. Nat Rev Mol Cell Biol 13, 115–126 (2012). https://doi.org/10.1038/nrm3274

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