Dynamic regulation of histone H3 methylated at lysine 79 within a tissue-specific chromatin domain.
Post-translational modifications of individual lysine residues of core histones can exert unique functional consequences. For example, methylation of histone H3 at lysine 79 (H3-meK79) has been implicated recently in gene silencing in Saccharomyces cerevisiae. However, the distribution and function of H3-meK79 in mammalian chromatin are not known. We found that H3-meK79 has a variable distribution within the murine beta-globin locus in adult erythroid cells, being preferentially enriched at the active betamajor gene. By contrast, acetylated H3 and H4 and H3 methylated at lysine 4 were enriched both at betamajor and at the upstream locus control region. H3-meK79 was also enriched at the active cad gene, whereas the transcriptionally inactive loci necdin and MyoD1 contained very little H3-meK79. As the pattern of H3-meK79 at the beta-globin locus differed between adult and embryonic erythroid cells, establishment and/or maintenance of H3-meK79 was developmentally dynamic. Genetic complementation analysis in null cells lacking the erythroid and megakaryocyte-specific transcription factor p45/NF-E2 showed that p45/NF-E2 preferentially establishes H3-meK79 at the betamajor promoter. These results support a model in which H3-meK79 is strongly enriched in mammalian chromatin at active genes but not uniformly throughout active chromatin domains. As H3-meK79 is highly regulated at the beta-globin locus, we propose that the murine ortholog of Disruptor of Telomeric Silencing-1-like (mDOT1L) methyltransferase, which synthesizes H3-meK79, regulates beta-globin transcription.
Im
Hogune
H
Molecular and Cellular Pharmacology Program, Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706, USA.
Park
Changwon
C
Feng
Qin
Q
Johnson
Kirby D
KD
Kiekhaefer
Carol M
CM
Choi
Kyunghee
K
Zhang
Yi
Y
Bresnick
Emery H
EH
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D020868:Gene Silencing; D005816:Genetic Complementation Test; D005914:Globins / Q000378:metabolism; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D051379:Mice; D008957:Models, Genetic; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D005914:Globins; D008239:Lysine