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Molecular and Cellular Biology, February 2005, p. 1511-1525, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1511-1525.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Chromatin Architecture near a Potential 3' End of the Igh Locus Involves Modular Regulation of Histone Modifications during B-Cell Development and In Vivo Occupancy at CTCF Sites

Francine E. Garrett,1 Alexander V. Emelyanov,1 Manuel A. Sepulveda,1 Patrick Flanagan,2 Sabrina Volpi,1 Fubin Li,3 Dmitry Loukinov,2 Laurel A. Eckhardt,3 Victor V. Lobanenkov,2 and Barbara K. Birshtein1*

Department of Cell Biology, Albert Einstein College of Medicine, Bronx,1 Department of Biological Sciences, Hunter College, and Graduate School of City University of New York, New York, New York,3 Molecular Pathology Section, Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland2

Received 22 September 2004/ Returned for modification 28 October 2004/ Accepted 22 November 2004

The murine Igh locus has a 3' regulatory region (3' RR) containing four enhancers (hs3A, hs1,2, hs3B, and hs4) at DNase I-hypersensitive sites. The 3' RR exerts long-range effects on class switch recombination (CSR) to several isotypes through its control of germ line transcription. By measuring levels of acetylated histones H3 and H4 and of dimethylated H3 (K4) with chromatin immunoprecipitation assays, we found that early in B-cell development, chromatin encompassing the enhancers of the 3' RR began to attain stepwise modifications typical of an open conformation. The hs4 enhancer was associated with active chromatin initially in pro- and pre-B cells and then together with hs3A, hs1,2, and hs3B in B and plasma cells. Histone modifications were similar in resting splenic B cells and in splenic B cells induced by lipopolysaccharide to undergo CSR. From the pro-B-cell stage onward, the ~11-kb region immediately downstream of hs4 displayed H3 and H4 modifications indicative of open chromatin. This region contained newly identified DNase I-hypersensitive sites and several CTCF target sites, some of which were occupied in vivo in a developmentally regulated manner. The open chromatin environment of the extended 3' RR in mature B cells was flanked by regions associated with dimethylated K9 of histone H3. Together, these data suggest that 3' RR elements are located within a specific chromatin subdomain that contains CTCF binding sites and developmentally regulated modules.

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

Molecular and Cellular Biology, February 2005, p. 1511-1525, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1511-1525.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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