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Molecular and Cellular Biology, October 2008, p. 6123-6133, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00233-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Pax5 and Linker Histone H1 Coordinate DNA Methylation and Histone Modifications in the 3' Regulatory Region of the Immunoglobulin Heavy Chain Locus{triangledown} ,{dagger}

Vincenzo Giambra,1,{ddagger} Sabrina Volpi,1 Alexander V. Emelyanov,1 David Pflugh,2,§ Alfred L. M. Bothwell,2 Paolo Norio,1,¶ Yuhong Fan,1,|| Zhongliang Ju,1 Arthur I. Skoultchi,1 Richard R. Hardy,3 Domenico Frezza,4 and Barbara K. Birshtein1*

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520,2 Division of Basic Science, Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, Pennsylvania 19111,3 Department of Biology Enrico Calef, University of Tor Vergata, Rome, Italy4

Received 12 February 2008/ Returned for modification 31 March 2008/ Accepted 10 July 2008

The 3' regulatory region (3' RR) of the murine immunoglobulin heavy chain (IgH) locus contains multiple DNase I-hypersensitive (hs) sites. Proximal sites hs3A, hs1.2, and hs3B are located in an extensive palindromic region and together with hs4 are associated with enhancers involved in the expression and class switch recombination of IgH genes. Distal hs5, -6, and -7 sites located downstream of hs4 comprise a potential insulator for the IgH locus. In pro-B cells, hs4 to -7 are associated with marks of active chromatin, while hs3A, hs1.2, and hs3B are not. Our analysis of DNA methylation-sensitive restriction sites of the 3' RR has revealed a similar modular pattern in pro-B cells; hs4 to -7 sites are unmethylated, while the palindromic region is methylated. This modular pattern of DNA methylation and histone modifications appears to be determined by at least two factors: the B-cell-specific transcription factor Pax5 and linker histone H1. In pre-B cells, a region beginning downstream of hs4 and extending into hs5 showed evidence of allele-specific demethylation associated with the expressed heavy chain allele. Palindromic enhancers become demethylated later in B-cell differentiation, in B and plasma cells.

* Corresponding author. Mailing address: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: (718) 430-2291. Fax: (718) 430-8574. E-mail: birshtei{at}aecom.yu.edu

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Department of Pathology, BC Cancer Research Centre, Vancouver V5Z 1L3, Canada.

§ Present address: Centocor R & D, Inc., Department of Immunobiology, Radnor, PA 19087.

Present address: Department of Medicine (Oncology), Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10467.

|| Present address: School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0363.

Molecular and Cellular Biology, October 2008, p. 6123-6133, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00233-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Vincent-Fabert, C., Truffinet, V., Fiancette, R., Cogne, N., Cogne, M., Denizot, Y. (2009). Ig Synthesis and Class Switching Do Not Require the Presence of the hs4 Enhancer in the 3' IgH Regulatory Region. J. Immunol. 182: 6926-6932 [Abstract] [Full Text]  


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