A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals

Genes Dev. 2020 Nov 1;34(21-22):1493-1502. doi: 10.1101/gad.339762.120. Epub 2020 Oct 8.


Catalytic-inactivating mutations within the Drosophila enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.

Keywords: COMPASS; chromatin; epigenetics; transcription.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Conserved Sequence / genetics*
  • DNA-Binding Proteins / genetics*
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics*
  • Gene Deletion
  • Gene Expression Regulation / genetics
  • Genes, Lethal / genetics*
  • HCT116 Cells
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Oxidoreductases, N-Demethylating / genetics*
  • Protein Domains
  • Protein Stability


  • DNA-Binding Proteins
  • Drosophila Proteins
  • KMT2C protein, human
  • Oxidoreductases, N-Demethylating
  • UTX protein, Drosophila
  • Histone-Lysine N-Methyltransferase
  • MLL4 protein, human
  • TRR protein, Drosophila