RESUMO
The activity of rRNA genes (rDNA) is regulated by pathways that target the transcription machinery or alter the epigenetic state of rDNA. Previous work has established that downregulation of rRNA synthesis in quiescent cells is accompanied by upregulation of PAPAS, a long noncoding RNA (lncRNA) that recruits the histone methyltransferase Suv4-20h2 to rDNA, thus triggering trimethylation of H4K20 (H4K20me3) and chromatin compaction. Here, we show that upregulation of PAPAS in response to hypoosmotic stress does not increase H4K20me3 because of Nedd4-dependent ubiquitinylation and proteasomal degradation of Suv4-20h2. Loss of Suv4-20h2 enables PAPAS to interact with CHD4, a subunit of the chromatin remodeling complex NuRD, which shifts the promoter-bound nucleosome into the transcriptional "off" position. Thus, PAPAS exerts a "stress-tailored" dual function in rDNA silencing, facilitating either Suv4-20h2-dependent chromatin compaction or NuRD-dependent changes in nucleosome positioning.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Genes de RNAr , Histona-Lisina N-Metiltransferase/genética , Nucleossomos/química , Pressão Osmótica , RNA Longo não Codificante/genética , Ubiquitina-Proteína Ligases/genética , Animais , Montagem e Desmontagem da Cromatina , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Regulação da Expressão Gênica , Células HEK293 , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos , Células NIH 3T3 , Ubiquitina-Proteína Ligases Nedd4 , Nucleossomos/metabolismo , Nucleossomos/ultraestrutura , Concentração Osmolar , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Transcrição Gênica , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
A complex network of regulatory pathways links transcription to cell growth and proliferation. Here we show that cellular quiescence alters chromatin structure by promoting trimethylation of histone H4 at lysine 20 (H4K20me3). In contrast to pericentric or telomeric regions, recruitment of the H4K20 methyltransferase Suv4-20h2 to rRNA genes and IAP elements requires neither trimethylation of H3K9 nor interaction with HP1 proteins but depends on long noncoding RNAs (lncRNAs) that interact with Suv4-20h2. Growth factor deprivation and terminal differentiation lead to upregulation of these lncRNAs, increase in H4K20me3, and chromatin compaction. The results uncover a lncRNA-mediated mechanism that guides Suv4-20h2 to specific genomic loci to establish a more compact chromatin structure in growth-arrested cells.
