Document Detail


The leukemia-associated Mllt10/Af10-Dot1l are Tcf4/β-catenin coactivators essential for intestinal homeostasis.
MedLine Citation:
PMID:  21103407     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Wnt signaling maintains the undifferentiated state of intestinal crypt progenitor cells by inducing the formation of nuclear TCF4/β-catenin complexes. In colorectal cancer, activating mutations in Wnt pathway components cause inappropriate activation of TCF4/β-catenin-driven transcription. Despite the passage of a decade after the discovery of TCF4 and β-catenin as the molecular effectors of the Wnt signal, few transcriptional activators essential and unique to the regulation of this transcription program have been found. Using proteomics, we identified the leukemia-associated Mllt10/Af10 and the methyltransferase Dot1l as Tcf4/β-catenin interactors in mouse small intestinal crypts. Mllt10/Af10-Dot1l, essential for transcription elongation, are recruited to Wnt target genes in a β-catenin-dependent manner, resulting in H3K79 methylation over their coding regions in vivo in proliferative crypts of mouse small intestine in colorectal cancer and Wnt-inducible HEK293T cells. Depletion of MLLT10/AF10 in colorectal cancer and Wnt-inducible HEK293T cells followed by expression array analysis identifies MLLT10/AF10 and DOT1L as essential activators to a large extent dedicated to Wnt target gene regulation. In contrast, previously published β-catenin coactivators p300 and BRG1 displayed a more pleiotropic target gene expression profile controlling Wnt and other pathways. tcf4, mllt10/af10, and dot1l are co-expressed in Wnt-driven tissues in zebrafish and essential for Wnt-reporter activity. Intestinal differentiation defects in apc-mutant zebrafish can be rescued by depletion of Mllt10 and Dot1l, establishing these genes as activators downstream of Apc in Wnt target gene activation in vivo. Morpholino-depletion of mllt10/af10-dot1l in zebrafish results in defects in intestinal homeostasis and a significant reduction in the in vivo expression of direct Wnt target genes and in the number of proliferative intestinal epithelial cells. We conclude that Mllt10/Af10-Dot1l are essential, largely dedicated activators of Wnt-dependent transcription, critical for maintenance of intestinal proliferation and homeostasis. The methyltransferase DOT1L may present an attractive candidate for drug targeting in colorectal cancer.
Authors:
Tokameh Mahmoudi; Sylvia F Boj; Pantelis Hatzis; Vivian S W Li; Nadia Taouatas; Robert G J Vries; Hans Teunissen; Harry Begthel; Jeroen Korving; Shabaz Mohammed; Albert J R Heck; Hans Clevers
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-16
Journal Detail:
Title:  PLoS biology     Volume:  8     ISSN:  1545-7885     ISO Abbreviation:  PLoS Biol.     Publication Date:  2010  
Date Detail:
Created Date:  2010-11-24     Completed Date:  2011-01-31     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101183755     Medline TA:  PLoS Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e1000539     Citation Subset:  IM    
Affiliation:
Hubrecht Institute and University Medical Centre Utrecht, Utrecht, The Netherlands. t.mahmoudi@erasmusmc.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
Cell Line
Cell Proliferation
DNA Methylation
Homeostasis / physiology*
Humans
Intestine, Small / pathology,  physiology*
Leukemia / physiopathology*
Methyltransferases / genetics,  physiology*
Mice
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics,  physiology*
Transcription, Genetic
Zebrafish / genetics
beta Catenin / metabolism*
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; 0/Mllt10 protein, mouse; 0/Tcf4 protein, mouse; 0/Transcription Factors; 0/beta Catenin; EC 2.1.1.-/Dot1l protein, mouse; EC 2.1.1.-/Methyltransferases
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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