Abstract
The interplay between methylation and demethylation of histone lysine residues is an essential component of gene expression regulation and there is considerable interest in elucidating the roles of proteins involved. Here we report that histone demethylase KDM4A/JMJD2A, which is involved in the regulation of cell proliferation and is overexpressed in some cancers, interacts with RNA Polymerase I, associates with active ribosomal RNA genes and is required for serum-induced activation of rDNA transcription. We propose that KDM4A controls the initial stages of transition from ‘poised', non-transcribed rDNA chromatin into its active form. We show that PI3K, a major signalling transducer central for cell proliferation and survival, controls cellular localization of KDM4A and consequently its association with ribosomal DNA through the SGK1 downstream kinase. We propose that the interplay between PI3K/SGK1 signalling cascade and KDM4A constitutes a mechanism by which cells adapt ribosome biogenesis level to the availability of growth factors and nutrients.
Highlights
The interplay between methylation and demethylation of histone lysine residues is an essential component of gene expression regulation and there is considerable interest in elucidating the roles of proteins involved
In the absence of siRNA depletion of KDM4A, we observed that cells expressing inactive KDM4A exhibited decreased levels of Ribosomal DNA (rDNA) transcription compared with wild type showing its dominantnegative effect (Supplementary Fig. 8b,c). These results indicate that KDM4A demethylase activity is required for efficient activation of ribosomal RNA (rRNA) synthesis and that the inactive KDM4A functions as a dominant-negative mutant, suggesting the importance of changes in the methylation status of KDM4A substrates at rDNA genes
Since we showed that KDM4A protein levels increase upon serum refeeding, we tested if PI3K, mTOR and MAPK pathway can regulate the stability of KDM4A
Summary
The interplay between methylation and demethylation of histone lysine residues is an essential component of gene expression regulation and there is considerable interest in elucidating the roles of proteins involved. We report that histone demethylase KDM4A/ JMJD2A, which is involved in the regulation of cell proliferation and is overexpressed in some cancers, interacts with RNA Polymerase I, associates with active ribosomal RNA genes and is required for serum-induced activation of rDNA transcription. Transcription of rRNA genes by RNA Polymerase I (Pol-I) is a key stage of ribosome biogenesis is directly linked to cell growth and proliferation and is regulated by a variety of signalling cascades including PI3K, mTOR and MAPK pathways[5,6]. How chromatin architecture is controlled by growth factors/nutrients is still poorly understood despite continued efforts In this manuscript, we report the involvement of the histone demethylase KDM4A in the regulation of rDNA transcription. It was recently shown that KDM4A regulates protein translation in the cytosol[17]
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