|
| Status |
Public on Oct 19, 2012 |
| Title |
Global gene expression analysis of Dot1l-deficient and control intestinal villus cells in mouse |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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 DOT1L-mediated 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 mRNA expression levels but not with Wnt-responsive genes per se. Selective Dot1l disruption in Lgr5+ stem cells or in all intestinal epithelial cells eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. 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.
|
| |
|
| Overall design |
Examination of differential gene expression between Dot1l control (Dot1 f/f) and Dot1l mutant (Villin-Cre, Dot1l f/f) villus cells.
|
| |
|
| Contributor(s) |
Ho LL, Sinha AU, Armstrong SA, Shivdasani R |
| Citation(s) |
23428873 |
| Submission date |
Oct 19, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Amit Sinha |
| E-mail(s) |
amit.sinha@childrens.harvard.edu
|
| Phone |
617-582-7579
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Pediatric Oncology
|
| Lab |
Armstrong Lab
|
| Street address |
44 Binney St
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02135 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (2) |
|
| This SubSeries is part of SuperSeries: |
| GSE41543 |
DOT1L-mediated H3K79 methylation in chromatin is dispensable for Wnt pathway-specific and other intestinal epithelial functions |
|
| Relations |
| BioProject |
PRJNA178007 |
| SRA |
SRP016565 |
