Histone H3 tail positioning and acetylation by the c-Myb but not the v-Myb DNA-binding SANT domain.
The c-Myb transcription factor coordinates proliferation and differentiation of hematopoietic precursor cells. Myb has three consecutive N-terminal SANT-type repeat domains (R1, R2, R3), two of which (R2, R3) form the DNA-binding domain (DBD). Three amino acid substitutions in R2 alter the way Myb regulates genes and determine the leukemogenicity of the retrovirally transduced v-Myb oncogene. The molecular mechanism of how these mutations unleash the leukemogenic potential of Myb is unknown. Here we demonstrate that the c-Myb-DBD binds to the N-terminal histone tails of H3 and H3.3. C-Myb binding facilitates histone tail acetylation, which is mandatory during activation of prevalent differentiation genes in conjunction with CCAAT enhancer-binding proteins (C/EBP). Leukemogenic mutations in v-Myb eliminate the interaction with H3 and acetylation of H3 tails and abolish activation of endogenous differentiation genes. In primary v-myb-transformed myeloblasts, pharmacologic enhancement of H3 acetylation restored activation of differentiation genes and induced cell differentiation. Our data link a novel chromatin function of c-Myb with lineage-specific expression of differentiation genes and relate the loss of this function with the leukemic conversion of Myb.
Mo
Xianming
X
Max-Delbrueck-Center for Molecular Medicine, 13092 Berlin, Germany.
Kowenz-Leutz
Elisabeth
E
Laumonnier
Yves
Y
Xu
Hong
H
Leutz
Achim
A
D000107:Acetylation; D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002645:Chickens; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D042381:Granulocyte Precursor Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D020626:Oncogene Proteins v-myb / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae; D014161:Transduction, Genetic / Q000379:methods
D023081:CCAAT-Binding Factor; D002843:Chromatin; D006657:Histones; D020626:Oncogene Proteins v-myb; D020598:Proto-Oncogene Proteins c-myb