Mammalian Trithorax and polycomb-group homologues are antagonistic regulators of homeotic development.
Control of cell identity during development is specified in large part by the unique expression patterns of multiple homeobox-containing (Hox) genes in specific segments of an embryo. Trithorax and Polycomb-group (Trx-G and Pc-G) proteins in Drosophila maintain Hox expression or repression, respectively. Mixed lineage leukemia (MLL) is frequently involved in chromosomal translocations associated with acute leukemia and is the one established mammalian homologue of Trx. Bmi-1 was first identified as a collaborator in c-myc-induced murine lymphomagenesis and is homologous to the Drosophila Pc-G member Posterior sex combs. Here, we note the axial-skeletal transformations and altered Hox expression patterns of Mll-deficient and Bmi-1-deficient mice were normalized when both Mll and Bmi-1 were deleted, demonstrating their antagonistic role in determining segmental identity. Embryonic fibroblasts from Mll-deficient compared with Bmi-1-deficient mice demonstrate reciprocal regulation of Hox genes as well as an integrated Hoxc8-lacZ reporter construct. Reexpression of MLL was able to overcome repression, rescuing expression of Hoxc8-lacZ in Mll-deficient cells. Consistent with this, MLL and BMI-I display discrete subnuclear colocalization. Although Drosophila Pc-G and Trx-G members have been shown to maintain a previously established transcriptional pattern, we demonstrate that MLL can also dynamically regulate a target Hox gene.
Hanson
R D
RD
Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Hess
J L
JL
Yu
B D
BD
Ernst
P
P
van Lohuizen
M
M
Berns
A
A
van der Lugt
N M
NM
Shashikant
C S
CS
Ruddle
F H
FH
Seto
M
M
Korsmeyer
S J
SJ
D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities; D004268:DNA-Binding Proteins / Q000502:physiology*; D029721:Drosophila Proteins; D005314:Embryonic and Fetal Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005801:Genes, Homeobox; D011495:Histone-Lysine N-Methyltransferase; D019476:Insect Proteins / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D011519:Proto-Oncogenes; D012097:Repressor Proteins; D014157:Transcription Factors
C489421:Bmi1 protein, mouse; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D009687:Nuclear Proteins; C066770:Pc protein, Drosophila; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C063460:Trl protein, Drosophila; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D063150:Polycomb Repressive Complex 1