Meis cofactors control HDAC and CBP accessibility at Hox-regulated promoters during zebrafish embryogenesis.
Hox proteins form complexes with Pbx and Meis cofactors to control gene expression, but the role of Meis is unclear. We demonstrate that Hoxb1-regulated promoters are highly acetylated on histone H4 (AcH4) and occupied by Hoxb1, Pbx, and Meis in zebrafish tissues where these promoters are active. Inhibition of Meis blocks gene expression and reduces AcH4 levels at these promoters, suggesting a role for Meis in maintaining AcH4. Within Hox transcription complexes, Meis binds directly to Pbx and we find that this binding displaces histone deacetylases (HDACs) from Hoxb1-regulated promoters in zebrafish embryos. Accordingly, Pbx mutants that cannot bind Meis act as repressors by recruiting HDACs and reducing AcH4 levels, while Pbx mutants that bind neither HDAC nor Meis are constitutively active and recruit CBP to increase AcH4 levels. We conclude that Meis acts, at least in part, by controlling access of HDAC and CBP to Hox-regulated promoters.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, LRB822, Worcester, MA 01605, USA.
Seong-Kyu
SK
Choe
Peiyuan
P
Lu
Mako
M
Nakamura
Jinhyup
J
Lee
Charles G
CG
Sagerström
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000502:physiology*; D047108:Embryonic Development; D018507:Gene Expression Regulation, Developmental; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; C101121:HOXB1 homeodomain protein; D006657:Histones; D018398:Homeodomain Proteins; C102642:Meis3 protein, zebrafish; C486619:Pbx4 protein, zebrafish; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D008156:Luciferases; D050882:CREB-Binding Protein; C488363:HDAC1 protein, zebrafish; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases