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

Histone modifications such as lysine methylation affect chromatin structure and gene expression. Histone methylation can be reversed by the JmjC-domain family of histone demethylases. One such histone demethylase, JHDM1B, has been suggested to be a tumour suppressor. In this issue Frescas et al. confirm a probable role for JHDM1B in cancer development. JHDM1B is shown to repress expression of ribosomal RNA genes, via the demethylation of the trimethylated lysine 4 residue of histone H3. JHDM1B also influences cell growth and proliferation, suggesting that reduced levels of JHDM1B promote tumour development. The histone demethylase JHDM1B represses expression of the ribosomal RNA genes by demethylating the trimethylated lysine 4 residue of histone H3. This effect on rRNA expression is correlated with proliferation defects, and so reduced levels of JHDM1B may contribute to tumour development. 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.