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JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes

Abstract

JHDM1B is an evolutionarily conserved and ubiquitously expressed member of the JHDM (JmjC-domain-containing histone demethylase) family1,2,3. Because it contains an F-box motif, this protein is also known as FBXL10 (ref. 4). With the use of a genome-wide RNAi screen, the JHDM1B worm orthologue (T26A5.5) was identified as a gene that regulates growth5. In the mouse, four independent screens have identified JHDM1B as a putative tumour suppressor by retroviral insertion analysis6,7,8,9. Here we identify human JHDM1B as a nucleolar protein and show that JHDM1B preferentially binds the transcribed region of ribosomal DNA to repress the transcription of ribosomal RNA genes. We also show that repression of ribosomal RNA genes by JHDM1B is dependent on its JmjC domain, which is necessary for the specific demethylation of trimethylated lysine 4 on histone H3 in the nucleolus. In agreement with the notion that ribosomal RNA synthesis and cell growth are coupled processes, we show a JmjC-domain-dependent negative effect of JHDM1B on cell size and cell proliferation. Because aberrant ribosome biogenesis and the disruption of epigenetic control mechanisms contribute to cellular transformation, these results, together with the low levels of JHDM1B expression found in aggressive brain tumours, suggest a role for JHDM1B in cancer development.

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Figure 1: JHDM1B localizes to the nucleolus and associates with rDNA.
Figure 2: JHDM1B represses transcription of rRNA genes via the JmjC domain.
Figure 3: JHDM1B demethylates H3K4me3 on the rDNA locus.
Figure 4: JHDM1B inhibits cell growth and proliferation.

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Acknowledgements

We thank D. Reinberg, R. Santoro, J. Skaar and J. Wysocka for suggestions and/or critically reading the manuscript; L. Busino for helping with qRT–PCR analysis; and J. Wysocka and G. David for reagents. D.F. is grateful to A. Nans. M.P. is grateful to T. M. Thor for continuous support. This work was supported by an Emerald Foundation grant to D.G., a Fellowship from the American-Italian Cancer Foundation to D.G., a fellowship from the German Research Foundation to F.B., a Bernard B. Levine Foundation award to R.K.-N., and grants from the NIH to M.P.

Author Contributions D.F. performed all experiments, contributed to their planning and co-wrote the manuscript. D.G. contributed to the planning of experiments and discussing and interpreting results. F.B. conducted the fluorescence-activated cell sorting analysis. R.K.-N. generated JHDM1B mutants. M.P. coordinated the study and co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Michele Pagano.

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Frescas, D., Guardavaccaro, D., Bassermann, F. et al. JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature 450, 309–313 (2007). https://doi.org/10.1038/nature06255

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