Affiliation:
1. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA
2. Department of Physiology, Keio University School of Medicine, Tokyo, Japan
Abstract
ABSTRACT
The human MLL genes (
MLL1
to
MLL4
) and their
Drosophila
orthologs,
trithorax
(
trx
) and
trithorax
related
(
trr
), encode proteins capable of methylating histone H3 on lysine 4. MLL1 and MLL2 are most similar to
trx
, while MLL3 and MLL4 are more closely related to
trr
. Several MLL genes are mutated in human cancers, but how these proteins regulate cell proliferation is not known. Here we show that
trr
mutant cells have a growth advantage over their wild-type neighbors and display changes in the levels of multiple proteins that regulate growth and cell division, including Notch, Capicua, and cyclin B.
trr
mutant clones display markedly reduced levels of H3K4 monomethylation without obvious changes in the levels of H3K4 di- and trimethylation. The
trr
mutant phenotype resembles that of
Utx
, which encodes a H3K27 demethylase, consistent with the observation that Trr and Utx are found in the same protein complex. In contrast to the overgrowth displayed by
trr
mutant tissue,
trx
clones are underrepresented, express low levels of the antiapoptotic protein Diap1, and exhibit only modest changes in global levels of H3K4 methylation. Thus, in
Drosophila
eye imaginal discs, Trr, likely functioning together with Utx, restricts tissue growth. In contrast, Trx appears to promote cell survival.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
41 articles.
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