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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.

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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.


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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.).

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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.

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Correspondence to Shigeaki Kato.

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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).

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