Activator-mediated recruitment of the MLL2 methyltransferase complex to the beta-globin locus.
MLL-containing complexes methylate histone H3 at lysine 4 (H3K4) and have been implicated in the regulation of transcription. However, it is unclear how MLL complexes are targeted to specific gene loci. Here, we show that the MLL2 complex associates with the hematopoietic activator NF-E2 in erythroid cells and is important for H3K4 trimethylation and maximal levels of transcription at the beta-globin locus. Furthermore, recruitment of the MLL2 complex to the beta-globin locus is dependent upon NF-E2 and coincides spatio-temporally with NF-E2 binding during erythroid differentiation. Thus, a DNA-bound activator is important initially for guiding MLL2 to a particular genomic location. Interestingly, while the MLL2-associated subunit ASH2L is restricted to the beta-globin locus control region 38 kb upstream of the beta(maj)-globin gene, the MLL2 protein spreads across the beta-globin locus, suggesting a previously undefined mechanism by which an activator influences transcription and H3K4 trimethylation at a distance.
Demers
Celina
C
Sprott Center for Stem Cell Research, Ottawa Health Research Institute, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
Chaturvedi
Chandra-Prakash
CP
Ranish
Jeffrey A
JA
Juban
Gaetan
G
Lai
Patrick
P
Morle
Francois
F
Aebersold
Ruedi
R
Dilworth
F Jeffrey
FJ
Groudine
Mark
M
Brand
Marjorie
M
D000818:Animals; D002454:Cell Differentiation; D002457:Cell Extracts; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000172:deficiency; D041905:Erythroid Cells / Q000166:cytology; D005914:Globins / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism*; D051379:Mice; D008957:Models, Genetic; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000378:metabolism*; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency; D011485:Protein Binding; D021381:Protein Transport; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency; D014158:Transcription, Genetic
C120115:Ash2l protein, mouse; D002457:Cell Extracts; D004268:DNA-Binding Proteins; D006657:Histones; D050984:NF-E2 Transcription Factor, p45 Subunit; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D005914:Globins; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse
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