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J. Biol. Chem., Vol. 280, Issue 42, 35261-35271, October 21, 2005

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Identification and Characterization of a Novel Human Histone H3 Lysine 36-specific Methyltransferase^*

Xiao-Jian Sun¶1, Ju Wei12, Xin-Yan Wu13, Ming Hu1, Lan Wang¶, Hai-Hong Wang, Qing-Hua Zhang, Sai-Juan Chen¶, Qiu-Hua Huang4, and Zhu Chen¶4

From the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Second Medical University, State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to Shanghai Second Medical University, and ^¶Graduate School of the Chinese Academy of Sciences, Shanghai 200025, China

Histone methylation plays an important role in eukaryotic transcriptional regulation. A number of histone methyltransferases (HMTases) with distinct functions have been identified. The HSPC069/HYPB gene was originally isolated from the human hematopoietic stem/progenitor cells (HSPCs), and it was also identified as a huntingtin interacting protein, implicated in the pathogenesis of Huntington disease (HD). However, its biochemical function is poorly understood. Here we report the structural and functional characterization of the huntingtin interacting protein B (HYPB). 1) The triplicate AWS-SET-PostSET domains mediate a histone H3 lysine 36 specific HMTase activity. 2) A low charged region that is rich in glutamine and proline has been characterized as a novel transcriptional activation domain. The structural features of this region are evolutionarily conserved in vertebrates. 3) Coimmunoprecipitation assays indicate that HYPB protein associates with hyperphosphorylated RNA polymerase II (RNAPII) but not the unphosphorylated form. Furthermore, the RNAPII-association region of HYPB protein has been identified to encompass the C-terminal 142 amino acids. Thus, our results suggest that HYPB HMTase may coordinate histone methylation and transcriptional regulation in mammals and open perspective for the further study of the potential roles of HYPB protein in hematopoiesis and pathogenesis of HD.

Received for publication, April 13, 2005 , and in revised form, August 22, 2005.

^* This work was supported in part by the National Natural Science Foundation of China (Grant 30370334), the Chinese National Key Basic Research Project (973), the Chinese National High Tech Program (863), and the Shanghai Leading Academic Discipline. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY576987.

¹ These authors contribute equally to this work.

² Present address: Dept. of Hematology, Shanghai First People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200080, China.

³ Present address: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231.

⁴ To whom correspondence may be addressed: Shanghai Inst. of Hematology, Ruijin Hospital, Shanghai Second Medical University, 197 Ruijin Rd. II, Shanghai 200025, China. Tel.: 86-21-64377859; Fax: 86-21-64743206; E-mail: zchen{at}stn.sh.cn (for Z. C.) or qiuhua_huang{at}etang.com (for Q.-H. H.).

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