MOZ and BMI1 play opposing roles during Hox gene activation in ES cells and in body segment identity specification in vivo.
Hox genes underlie the specification of body segment identity in the anterior-posterior axis. They are activated during gastrulation and undergo a dynamic shift from a transcriptionally repressed to an active chromatin state in a sequence that reflects their chromosomal location. Nevertheless, the precise role of chromatin modifying complexes during the initial activation phase remains unclear. In the current study, we examined the role of chromatin regulators during Hox gene activation. Using embryonic stem cell lines lacking the transcriptional activator MOZ and the polycomb-family repressor BMI1, we showed that MOZ and BMI1, respectively, promoted and repressed Hox genes during the shift from the transcriptionally repressed to the active state. Strikingly however, MOZ but not BMI1 was required to regulate Hox mRNA levels after the initial activation phase. To determine the interaction of MOZ and BMI1 in vivo, we interrogated their role in regulating Hox genes and body segment identity using Moz;Bmi1 double deficient mice. We found that the homeotic transformations and shifts in Hox gene expression boundaries observed in single Moz and Bmi1 mutant mice were rescued to a wild type identity in Moz;Bmi1 double knockout animals. Together, our findings establish that MOZ and BMI1 play opposing roles during the onset of Hox gene expression in the ES cell model and during body segment identity specification in vivo. We propose that chromatin-modifying complexes have a previously unappreciated role during the initiation phase of Hox gene expression, which is critical for the correct specification of body segment identity.
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia;
Bilal N
BN
Sheikh
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia;
Natalie L
NL
Downer
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and.
Belinda
B
Phipson
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia;
Hannah K
HK
Vanyai
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia;
Andrew J
AJ
Kueh
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and.
Davis J
DJ
McCarthy
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; and Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC 3052, Australia.
Gordon K
GK
Smyth
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; avoss@wehi.edu.au tthomas@wehi.edu.au.
Tim
T
Thomas
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; avoss@wehi.edu.au tthomas@wehi.edu.au.
Anne K
AK
Voss
D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
C489421:Bmi1 protein, mouse; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse; D063150:Polycomb Repressive Complex 1
BMI1; MYST; histone acetyltransferase; lysine acetyltransferase; polycomb