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Mol Cell Biol, May 1998, p. 2617-2628, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The HMG Domain Protein SSRP1/PREIIBF Is Involved in Activation of the Human Embryonic beta -Like Globin Gene

Michael A. Dyer,1,dagger Patrick J. Hayes,1,Dagger and Margaret H. Baron1,*,Dagger

Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138

Received 29 December 1997/Returned for modification 3 February 1998/Accepted 9 February 1998

The human embryonic beta -like globin (varepsilon -globin) gene is expressed in primitive erythroid cells of the yolk sac during the first few weeks of development. We have previously shown that developmental stage-specific expression of the varepsilon -globin gene is mediated by multiple positive and negative regulatory elements upstream of the start of transcription. Of particular interest is one positive regulatory element, PRE II, that works together with other elements (PRE I and PRE V) to confer developmental stage- and/or tissue-specific expression on a minimal promoter. An ~85- to 90-kDa PRE II binding factor (PREIIBF) was identified in the nuclei of erythroid cells and shown to bind specifically to a novel 19-bp region within PRE II; binding of this protein to PRE II resulted in bending of the target DNA and was required for promoter activation. In this report, we present the cDNA expression cloning of PREIIBF. The cDNA encodes a previously identified member of the HMG domain family of DNA binding proteins termed SSRP1. By a number of biochemical and immunological criteria, recombinant SSRP1 appears to be identical to the PREII binding factor from erythroid nuclei. A hallmark of HMG domain proteins is their ability to bend their target DNAs; therefore, as we speculated previously, DNA bending by SSRP1/PREIIBF may contribute to the mechanism by which PRE II synergizes with other regulatory elements located upstream and downstream. In contrast with reports from other investigators, we demonstrate that SSRP1 binds DNA with clear sequence specificity. Moreover, we show that SSRP1/PREIIBF lacks a classical activation domain but that binding by this protein to PRE II is required for activation of a minimal promoter in stable erythroid cell lines. These studies provide the first evidence that SSRP1 plays a role in transcriptional regulation. SSRP1/PREIIBF may serve an architectural function by helping to coordinate the assembly of a multiprotein complex required for stage-specific regulation of the human varepsilon -globin gene.

* Corresponding author. Mailing address: The Mount Sinai School of Medicine, Box 1079, East Building 11-70B, 1425 Madison Ave., New York, NY 10029. Phone: (212) 824-7420. Fax: (212) 849-2442. E-mail: mhbaron{at}msvax.mssm.edu.

dagger Present address: Department of Genetics, Harvard Medical School, Boston, MA 02115.

Dagger Present address: Department of Medicine, Brookdale Center for Developmental and Molecular Biology, Ruttenberg Cancer Center, and Institute for Gene Therapy and Molecular Medicine, The Mount Sinai School of Medicine, New York, NY 10029.

Mol Cell Biol, May 1998, p. 2617-2628, Vol. 18, No. 5
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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