Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase.
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.
Sun
Xiao-Jian
XJ
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Second Medical University, Shanghai 200025, China.
Wei
Ju
J
Wu
Xin-Yan
XY
Hu
Ming
M
Wang
Lan
L
Wang
Hai-Hong
HH
Zhang
Qing-Hua
QH
Chen
Sai-Juan
SJ
Huang
Qiu-Hua
QH
Chen
Zhu
Z
D000595:Amino Acid Sequence; D002460:Cell Line; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000502:physiology*; D004926:Escherichia coli / Q000378:metabolism; D019143:Evolution, Molecular; D005973:Glutamine / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry*; D006657:Histones / Q000737:chemistry*; D006801:Humans; D047468:Immunoprecipitation; D008239:Lysine / Q000737:chemistry*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010802:Phylogeny; D010957:Plasmids / Q000378:metabolism; D011392:Proline / Q000737:chemistry; D011485:Protein Binding; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D004268:DNA-Binding Proteins; D006657:Histones; C435268:Huntingtin-interacting protein p231HBP; D011994:Recombinant Proteins; D005973:Glutamine; D011392:Proline; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D005982:Glutathione Transferase; D012319:RNA Polymerase II; D008239:Lysine