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J. Biol. Chem., Vol. 282, Issue 18, 13419-13428, May 4, 2007

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Identification and Characterization of the Human Set1B Histone H3-Lys⁴ Methyltransferase Complex^*

Jeong-Heon Lee, Courtney M. Tate¹, Jin-Sam You, and David G. Skalnik²

From the Wells Center for Pediatric Research, Section of Pediatric Hematology/Oncology, Departments of Pediatrics and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and the Indiana Centers for Applied Protein Sciences, Indianapolis, Indiana 46202

We previously identified a mammalian Set1A complex analogous to the yeast Set1/COMPASS histone H3-Lys4 methyltransferase complex (Lee, J.-H., and Skalnik, D. G. (2005) J. Biol. Chem. 280, 41725–41731). Data base analysis indicates that human Set1A protein shares 39% identity with an uncharacterized SET domain protein, KIAA1076, hereafter denoted Set1B. Immunoprecipitation and mass spectrometry reveal that Set1B associates with a 450 kDa complex that contains all five non-catalytic components of the Set1A complex, including CFP1, Rbbp5, Ash2, Wdr5, and Wdr82. These data reveal two human protein complexes that differ only in the identity of the catalytic histone methyltransferase. In vitro assays demonstrate that the Set1B complex is a histone methyltransferase that produces trimethylated histone H3 at Lys⁴. Both Set1A and Set1B are widely expressed. Inducible expression of the carboxyl terminus of either Set1A or Set1B decreases steady-state levels of both endogenous Set1A and Set1B protein, but does not alter the expression of the non-catalytic components of the Set1 complexes. A 123-amino acid fragment upstream of the Set1A SET domain is necessary for interaction with CFP1, Ash2, Rbbp5, and Wdr5. This protein domain is also required to mediate feedback inhibition of Set1A and Set1B expression, which is a consequence of reduced Set1A and Set1B stability when not associated with the methyltransferase complex. Confocal microscopy reveals that Set1A and Set1B each localize to a largely non-overlapping set of euchromatic nuclear speckles, suggesting that Set1A and Set1B each bind to a unique set of target genes and thus make non-redundant contributions to the epigenetic control of chromatin structure and gene expression.

Received for publication, October 18, 2006 , and in revised form, February 26, 2007.

^* This work was supported in part by the Riley Children's Foundation, the Lilly Endowment, National Science Foundation Grant MCB-0344870 (to D. G. S.), and a Showalter Trust award (to J.-H. L). Mass spectrometry analysis was performed at the Indiana Centers for Applied Protein Sciences with support in part from the Indiana 21st Century Research and Technology Fund. 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.

¹ Supported by a fellowship from the Immunology and Infectious Diseases Training Program National Institutes of Health Grant T32 AI060519.

² To whom correspondence should be addressed: Cancer Research Bldg., Rm. 327, 1044 West Walnut St., Indianapolis, IN 46202. Tel.: 317-274-8977; Fax: 317-274-8928; E-mail: dskalnik{at}iupui.edu.

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