A multistep mechanism for the activation of rearrangement in the immune system.
Rearrangement of immune receptor loci is a developmentally controlled process that takes place exclusively in lymphoid cells. We have used a stable transfection system in pre-B cells to show that DNA methylation brings about histone underacetylation, histone H3(K9) methylation, DNaseI resistance, and strong inhibition of both transcription and recombination. Strikingly, this repression is maintained in dividing cells even after removal of the original methyl groups responsible for its establishment, but in this state, rearrangement can now be induced by reacetylation of local histones using the drug Trichostatin A. This same combination of demethylation and histone acetylation is also required to activate germline transcription and recombination from the endogenous kappa locus in vivo. These results indicate that the regulation of rearrangement is carried out by a multilayered synergistic process.
Ji
Yanhong
Y
Department of Experimental Medicine, Hebrew University Medical School, Jerusalem 91120, Israel.
Zhang
Jianmin
J
Lee
Alfred Ian
AI
Cedar
Howard
H
Bergman
Yehudit
Y
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D007107:Immune System; D008164:Luminescent Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D008836:Micrococcal Nuclease / Q000378:metabolism; D008957:Models, Genetic; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D045567:VDJ Recombinases
D002843:Chromatin; D006657:Histones; D006877:Hydroxamic Acids; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; C012589:trichostatin A; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases; D003850:Deoxyribonuclease I; D008836:Micrococcal Nuclease