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J. Biol. Chem., Vol. 278, Issue 43, 42106-42114, October 24, 2003

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HMGA1 Co-activates Transcription in B Cells through Indirect Association with DNA^*

Kevin M. McCarthy, Daniel McDevit, Amy Andreucci, Raymond Reeves¶, and Barbara S. Nikolajczyk||

From the Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, 02118, the partment of Medicine, Immunobiology Unit, Evans Memorial Department of Clinical Research, Boston Medical Center, Boston, Massachusetts 02118, and the ^¶Department of Biochemistry and Biophysics, Washington State University, Pullman, Washington 99164-4660

The immunoglobulin heavy chain enhancer, or µ enhancer, is required for B cell development. Only the appropriate combination of transcription factors results in B cell-specific enhancer activation. HMGA1 (formerly (HMG-I(Y)) is a proposed co-activator of the ETS transcription factors required for µ enhancer activity. HMGA1 associates with the ETS factor PU.1, resulting in changes in PU.1 structure, and enhanced transcriptional synergy with Ets-1 on the µ enhancer in nonlymphoid cells. New data show HMGA1 directly interacts with Ets-1 in addition to PU.1. In vitro HMGA1/Ets-1 interaction facilitates Ets-1/µ enhancer binding in the absence of an HMGA1·Ets-1·DNA complex. To address whether HMGA1 is present in the transcriptionally active µ nucleoprotein complex, we completed DNA pull-down assays to detect protein tethering in the context of protein/DNA interaction. Results show that HMGA1 is not tightly associated with µ enhancer DNA through PU.1 or Ets-1, despite strong associations between these proteins in solution. However, chromatin immunoprecipitation assays show HMGA1 associates with the endogenous enhancer in B cells. Furthermore, antisense HMGA1 substantially decreases µ enhancer activity in B cells. Taken together, these data suggest that HMGA1 functions as a transcriptional µ enhancer co-activator in B cells through indirect association with DNA.

Received for publication, August 5, 2003

This work is dedicated to the memory of Glenn Harris, a longtime mentor and friend.

^* This work was supported by NIH AI54611, The Evans Medical Foundation, an Arthritis Foundation grant (to B. N.), and NIH T32-CA64070 (to K. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. Tel.: 617-638-7019; Fax: 617-638-7140; E-mail: bnikol{at}medicine.bu.edu.

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