MLL targets SET domain methyltransferase activity to Hox gene promoters.
MLL, the human homolog of Drosophila trithorax, maintains Hox gene expression in mammalian embryos and is rearranged in human leukemias resulting in Hox gene deregulation. How MLL or MLL fusion proteins regulate gene expression remains obscure. We show that MLL regulates target Hox gene expression through direct binding to promoter sequences. We further show that the MLL SET domain is a histone H3 lysine 4-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity is associated with Hox gene activation and H3 (Lys4) methylation at cis-regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates Hox expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins.
Milne
Thomas A
TA
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Briggs
Scott D
SD
Brock
Hugh W
HW
Martin
Mary Ellen
ME
Gibbs
Denise
D
Allis
C David
CD
Hess
Jay L
JL
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003001:Cloning, Molecular; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000378:metabolism; D017931:DNA Primers / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D017931:DNA Primers; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D004247:DNA; D015254:DNA Modification Methylases; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse