TY  - GEN
ID  - heidok9945
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/9945/
N2  - In mammalian cells, actively transcribed rRNA genes (rDNA) exist in a euchromatic configuration, whereas silent rDNA repeats form a heterochromatic structure. A hallmark of active rDNA is methylation of histone H3 lysine K4 (H3K4me), while silent genes are characterized by methylation of histone H3 lysine K9 (H3K9me). The balance between H3K4me and H3K9me is established and maintained by the coordinated interplay of different histone methyltransferases and demethylases. Several histone H3K9 methyltransferases such as G9a, SETDB1 and Suv39H1, have been shown to modulate the chromatin structure of rRNA genes. However, the enzymes that remove repressive methyl groups from H3K9 at the rDNA promoter are yet unknown. In the present study, the function of two putative Jumonji-C (JmjC) domain-containing histone demethylases PHF2 (PHD finger protein 2) and PHF8 (PHD finger protein 8) has been characterized. Both PHF2 and PHF8 localize to nucleoli and are associated with active rRNA genes. Gain-of-function and loss-of-function experiments demonstrate that PHF2 and PHF8 activate rDNA transcription. Transcriptional activation depends on the presence of a functional PHD finger and the JmjC domain. Recruitment of PHF2 and PHF8 to rDNA is mediated by the interaction with the RNA polymerase I (Pol I) transcription machinery. In addition, the PHD fingers of PHF2 and PHF8 bind to the euchromatic histone mark, H3K4me3, which may facilitate the association of both proteins with active rDNA. Depletion of PHF8 leads to increased levels of the repressive marks H3K9me1 and H3K9me2 (H3K9me1/2) at the rDNA promoter, suggesting that PHF8 demethylates H3K9me1/2. In contrast, PHF2 shows no histone demethylase activity on itself but appears to antagonize a transcriptional repressor, the H3K4me3 demethylase KDM2B. The association of PHF2 with rDNA depends on PHF8, indicating that PHF2 and PHF8 function as a complex that is able to remove H3K9me1/2 and to maintain H3K4me3 at active rDNA repeats.  Mutations in the human PHF8 gene are associated with an inherited disease termed X-linked mental retardation (XLMR). As demonstrated in this study, an XLMR-associated point mutation in the JmjC domain of PHF8 (F279S) impairs the interaction with the Pol I transcription machinery, the nucleolar localization and PHF8-dependent transcriptional activation. Thus, impairment of PHF8-mediated activation of rDNA transcription might contribute to the development of XLMR.  Together, the results uncover an important function of PHF2 and PHF8 in nucleoli, adding a new layer of epigenetic regulation of rRNA genes. This regulation is vital for proper rRNA synthesis and its disruption is likely to cause severe diseases in humans. 
KW  - Transkription der rRNA-GenerDNA transciption
Y1  - 2009///
TI  - The Jumonji domain containing proteins PHF2 and PHF8 act in concert to stimulate transcription of rRNA genes
A1  - Feng, Weijun
AV  - public
ER  -