Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

PKA-dependent regulation of the histone lysine demethylase complex PHF2–ARID5B


Reversible histone methylation and demethylation are highly regulated processes that are crucial for chromatin reorganization and regulation of gene transcription in response to extracellular conditions. However, the mechanisms that regulate histone-modifying enzymes are largely unknown. Here, we characterized a protein kinase A (PKA)-dependent histone lysine demethylase complex, PHF2–ARID5B. PHF2, a jmjC demethylase, is enzymatically inactive by itself, but becomes an active H3K9Me2 demethylase through PKA-mediated phosphorylation. We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. This modification leads to targeting of the PHF2–ARID5B complex to its target promoters, where it removes the repressive H3K9Me2 mark. These findings suggest that the PHF2–ARID5B complex is a signal-sensing modulator of histone methylation and gene transcription, in which phosphorylation of PHF2 enables subsequent formation of a competent and specific histone demethylase complex.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Identification of the PHF2–ARID5B histone H3K9Me2 demethylase complex.
Figure 2: PKA-dependent complex assembly of PHF2–ARID5B.
Figure 3: PKA-dependent demethylase activity of the PHF2–ARID5B complex.
Figure 4: PKA-dependent promoter targeting of PHF2–ARID5B.
Figure 5: ARID5B directs PKA-dependent promoter targeting of PHF2.
Figure 6: PHF2–ARID5B co-activates HNF4α in liver of fasted mice.


  1. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  Article  Google Scholar 

  2. Ruthenburg, A. J., Li, H., Patel, D. J. & Allis, C. D. Multivalent engagement of chromatin modifications by linked binding modules. Nat. Rev. Mol. Cell Biol. 8, 983–994 (2007).

    CAS  Article  Google Scholar 

  3. Iwase, S. et al. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 128, 1077–1088 (2007).

    CAS  Article  Google Scholar 

  4. Klose, R. J., Kallin, E. M. & Zhang, Y. JmjC-domain-containing proteins and histone demethylation. Nat. Rev. Genet. 7, 715–727 (2006).

    CAS  Article  Google Scholar 

  5. Lee, M. G., Norman, J., Shilatifard, A. & Shiekhattar, R. Physical and functional association of a trimethyl H3K4 demethylase and Ring6a/MBLR, a polycomb-like protein. Cell 128, 877–887 (2007).

    CAS  Article  Google Scholar 

  6. Shi, Y. & Whetstine, J. R. Dynamic regulation of histone lysine methylation by demethylases. Mol. Cell 25, 1–14 (2007).

    CAS  Article  Google Scholar 

  7. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    CAS  Article  Google Scholar 

  8. Christensen, J. et al. RBP2 belongs to a family of demethylases, specific for tri- and dimethylated lysine 4 on histone 3. Cell 128, 1063–1076 (2007).

    CAS  Article  Google Scholar 

  9. Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 (2007).

    CAS  Article  Google Scholar 

  10. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    CAS  Article  Google Scholar 

  11. Ohtake, F. et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446, 562–566 (2007).

    CAS  Article  Google Scholar 

  12. Takada, I. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat. Cell Biol. 9, 1273–1285 (2007).

    CAS  Article  Google Scholar 

  13. Hasenpusch-Theil, K. et al. PHF2, a novel PHD finger gene located on human chromosome 9q22. Mamm. Genome 10, 294–298 (1999).

    CAS  Article  Google Scholar 

  14. Whitson, R. H., Huang, T. & Itakura, K. The novel Mrf-2 DNA-binding domain recognizes a five-base core sequence through major and minor-groove contacts. Biochem. Biophys. Res. Commun. 258, 326–331 (1999).

    CAS  Article  Google Scholar 

  15. Qi, H. H. et al. Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish brain and craniofacial development. Nature 466, 503–507 (2010).

    CAS  Article  Google Scholar 

  16. Liu, W. et al. PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression. Nature 466, 508–512 (2010).

    CAS  Article  Google Scholar 

  17. Tsukada, Y., Ishitani, T. & Nakayama, K. I. KDM7 is a dual demethylase for histone H3 Lys 9 and Lys 27 and functions in brain development. Genes Dev. 24, 432–437 (2010).

    CAS  Article  Google Scholar 

  18. Li, F. et al. Lid2 is required for coordinating H3K4 and H3K9 methylation of heterochromatin and euchromatin. Cell 135, 272–283 (2008).

    CAS  Article  Google Scholar 

  19. Lan, F. et al. S. pombe LSD1 homologs regulate heterochromatin propagation and euchromatic gene transcription. Mol. Cell 26, 89–101 (2007).

    CAS  Article  Google Scholar 

  20. Jiang, G. & Zhang, B. B. Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 284, E671–E678 (2003).

    CAS  Article  Google Scholar 

  21. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005).

    Article  Google Scholar 

  22. Mayr, B. & Montminy, M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol. 2, 599–609 (2001).

    CAS  Article  Google Scholar 

  23. Feige, J.N. & Auwerx, J. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 17, 292–301 (2007).

    CAS  Article  Google Scholar 

  24. Goodwin, B. et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol. Cell 6, 517–526 (2000).

    CAS  Article  Google Scholar 

  25. Lu, T. T. et al. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol. Cell 6, 507–515 (2000).

    CAS  Article  Google Scholar 

  26. Koo, S. H. et al. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109–1111 (2005).

    CAS  Article  Google Scholar 

  27. Rhee, J. et al. Regulation of hepatic fasting response by PPARgamma coactivator-1α (PGC-1): requirement for hepatocyte nuclear factor 4α in gluconeogenesis. Proc. Natl Acad. Sci. USA 100, 4012–4017 (2003).

    CAS  Article  Google Scholar 

  28. Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001).

    CAS  Article  Google Scholar 

  29. Fujiki, R. et al. GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459, 455–459 (2009).

    CAS  Article  Google Scholar 

  30. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    CAS  Article  Google Scholar 

  31. Rosenfeld, M. G., Lunyak, V. V. & Glass, C. K. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 20, 1405–1428 (2006).

    CAS  Article  Google Scholar 

  32. Unno, A. et al. TRRAP as a hepatic coactivator of LXR and FXR function. Biochem. Biophys. Res. Commun. 327, 933–938 (2005).

    CAS  Article  Google Scholar 

  33. Ohtake, F. et al. Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature 423, 545–550 (2003).

    CAS  Article  Google Scholar 

  34. Yokoyama, A., Takezawa, S., Schule, R., Kitagawa, H. & Kato, S. Transrepressive function of TLX requires the histone demethylase LSD1. Mol. Cell Biol. 28, 3995–4003 (2008).

    CAS  Article  Google Scholar 

  35. Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction. Nature 423, 550–555 (2003).

    CAS  Article  Google Scholar 

  36. Okada, M. et al. Switching of chromatin-remodelling complexes for oestrogen receptor-alpha. EMBO Rep. 9, 563–568 (2008).

    CAS  Article  Google Scholar 

  37. Fujiki, R. et al. Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J. 24, 3881–3894 (2005).

    CAS  Article  Google Scholar 

Download references


We thank D. D. Moore for critical discussion, R. Sato and J. Inoue for providing materials, N. Moriyama and S. Fujiyama for technical assistance and M. Yamaki for manuscript preparation. This work was supported in part by Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, MEXT, Japan, JSPS, and The Naito Foundation (to F.O. and S.K.).

Author information

Authors and Affiliations



A.B., F.O. and S.K. designed the study. A.B., F.O., Y.O., K.Y., M.O. and Y.I. carried out experiments. M.N., C.A.M., K.I., J.K. and M.B. carried out analyses and provided general support. F.O. and S.K. wrote the paper.

Corresponding author

Correspondence to Shigeaki Kato.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 3580 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Baba, A., Ohtake, F., Okuno, Y. et al. PKA-dependent regulation of the histone lysine demethylase complex PHF2–ARID5B. Nat Cell Biol 13, 668–675 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing