Structural insights into a novel histone demethylase PHF8

Lin Yu, Yang Wang, Shuo Huang, Jianjun Wang, Zengqin Deng, Qi Zhang, Wei Wu, Xingliang Zhang, Zhao Liu, Weimin Gong, Zhongzhou Chen

Research output: Contribution to journalArticleResearchpeer-review

47 Citations (Scopus)

Abstract

Dynamic regulation of histone methylation/demethylation plays an important role during development. Mutations and truncations in human plant homeodomain (PHD) finger protein 8 (PHF8) are associated with X-linked mental retardation and facial anomalies, such as a long face, broad nasal tip, cleft lip/cleft palate and large hands, yet its molecular function and structural basis remain unclear. Here, we report the crystal structures of the catalytic core of PHF8 with or without α-ketoglutarate (α-KG) at high resolution. Biochemical and structural studies reveal that PHF8 is a novel histone demethylase specific for di- and mono-methylated histone H3 lysine 9 (H3K9me2/1), but not for H3K9me3. Our analyses also reveal how human PHF8 discriminates between methylation states and achieves sequence specificity for methylated H3K9. The in vitro demethylation assay also showed that the F279S mutant observed in clinical patients possesses no demethylation activity, suggesting that loss of enzymatic activity is crucial for pathogenesis of PHF8 patients. Taken together, these results will shed light on the molecular mechanism underlying PHF8-associated developmental and neurological diseases.
Original languageEnglish
Pages (from-to)166-173
Number of pages8
JournalCell Research
Volume20
Issue number2
DOIs
Publication statusPublished - Feb 2010
Externally publishedYes

Keywords

  • Chromatin modification
  • Crystal structure
  • Facial anomalies
  • Histone demethylase
  • Methylated H3K9
  • PHF8 (PHD finger protein 8)
  • X-linked mental retardation (XLMR)

Cite this

Yu, L., Wang, Y., Huang, S., Wang, J., Deng, Z., Zhang, Q., Wu, W., Zhang, X., Liu, Z., Gong, W., & Chen, Z. (2010). Structural insights into a novel histone demethylase PHF8. Cell Research, 20(2), 166-173. https://doi.org/10.1038/cr.2010.8