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

Ryan Rickels, Lu Wang, Marta Iwanaszko, Patrick A. Ozark, Marc A. Morgan, Andrea Piunti, Natalia Khalatyan, Shimaa H.A. Soliman, Emily J. Rendleman, Jeffrey N. Savas, Edwin R. Smith, Ali Shilatifard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1493-1502
Number of pages10
JournalGenes and Development
Volume34
Issue number21-22
DOIs
StatePublished - Nov 1 2020
Externally publishedYes

Keywords

  • COMPASS
  • Chromatin
  • Epigenetics
  • Transcription

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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