A multistep mechanism for the activation of rearrangement in the immune system
- *Departments of Experimental Medicine and Cellular Biochemistry, Hebrew University Medical School, Jerusalem 91120, Israel; and †Section of Immunobiology, Yale University School of Medicine, New Haven, CT 08360
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Communicated by Gary Felsenfeld, National Institutes of Health, Bethesda, MD, May 1, 2003 (received for review August 7, 2002)
Abstract
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 κ locus in vivo. These results indicate that the regulation of rearrangement is carried out by a multilayered synergistic process.
Footnotes
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↵ ‡ To whom correspondence should be addressed. E-mail: yberg{at}md2.huji.ac.il.
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Abbreviations: RSS, recombination signal sequence; EGFP, enhanced GFP; TSA, Trichostatin A; LM-PCR, ligation-mediated PCR; ChIP, chromatin immunoprecipitation; DSB, double-strand breaks.
- Copyright © 2003, The National Academy of Sciences
