DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal Epithelial functions

Li Lun Ho, Amit Sinha, Michael Verzi, Kathrin M. Bernt, Scott A. Armstrong, Ramesh A. Shivdasani

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1Lmediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects, but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5+ mouse intestinal stem cells and mature intestinal villus epithelium correlated with expression levels of all transcripts and not with Wnt-responsive genes per se. Selective Dot1l disruption in Lgr5+ stem cells or in whole intestinal epithelium eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. The absence of methylated H3K79 did not impair health, intestinal homeostasis, or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l-null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes, and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo.

Original languageEnglish (US)
Pages (from-to)1735-1745
Number of pages11
JournalMolecular and cellular biology
Volume33
Issue number9
DOIs
StatePublished - May 1 2013

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Wnt Signaling Pathway
Methylation
Chromatin
Intestinal Mucosa
Genes
Stem Cells
Histone Code
Null Lymphocytes
Gene Rearrangement
Methyltransferases
Leukemia
Homeostasis
Epithelium
Genome
Apoptosis
Gene Expression
Health

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Ho, Li Lun ; Sinha, Amit ; Verzi, Michael ; Bernt, Kathrin M. ; Armstrong, Scott A. ; Shivdasani, Ramesh A. / DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal Epithelial functions. In: Molecular and cellular biology. 2013 ; Vol. 33, No. 9. pp. 1735-1745.
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DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal Epithelial functions. / Ho, Li Lun; Sinha, Amit; Verzi, Michael; Bernt, Kathrin M.; Armstrong, Scott A.; Shivdasani, Ramesh A.

In: Molecular and cellular biology, Vol. 33, No. 9, 01.05.2013, p. 1735-1745.

Research output: Contribution to journalArticle

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