Ribosomal DNA contributes to global chromatin regulation

Abstract

The 35S ribosomal RNA genes (rDNA) are organized as repeated arrays in many organisms. Epigenetic regulation of transcription of the rRNA results in only a subset of copies being transcribed, making rDNA an important model for understanding epigenetic chromatin modification. We have created an allelic series of deletions within the rDNA array of the Drosophila Y chromosome that affect nucleolus size and morphology, but do not limit steady-state rRNA concentrations. These rDNA deletions result in reduced heterochromatin-induced gene silencing elsewhere in the genome, and the extent of the rDNA deletion correlates with the loss of silencing. Consistent with this, chromosomes isolated from strains mutated in genes required for proper heterochromatin formation have very small rDNA arrays, reinforcing the connection between heterochromatin and the rDNA. In wild-type cells, which undergo spontaneous natural rDNA loss, we observed the same correlation between loss of rDNA and loss of heterochromatin-induced silencing, showing that the volatility of rDNA arrays may epigenetically influence gene expression through normal development and differentiation. We propose that the rDNA contributes to a balance between heterochromatin and euchromatin in the nucleus, and alterations in rDNA-induced or natural-affect this balance.Drosophila ͉ epigenetics ͉ heterochromatin ͉ nucleolus ͉ rDNA C hromatin within the nucleus is divided into cytologically heterochromatic and euchromatic compartments (1). This division reflects very different functional influences on gene expression (2). Many genes adopt more ''heterochromatin-like'' features when inactivated, including cytological appearance and association with specific proteins or post-translational modifications. This has led to hypotheses that similar mechanisms regulate facultatively inactivated genes or chromosomes, constitutively heterochromatic regions of the genome, and developmentally repressed genes (3). Understanding the interplay between heterochromatin and euchromatin, then, is fundamental in understanding the control of epigenetic regulation of the genome.Gene products involved in heterochromatin formation have been primarily identified by observing the effect of mutations on position effect variegation (PEV), which manifests as mosaic expression of a gene placed in a heterochromatic context. Many of these mutations act dominantly, thus the genes are thought to encode dosesensitive components of heterochromatin (4). Equally important to models of heterochromatin formation is the observation that the amount of constitutive heterochromatin in the nucleus affects heterochromatin-induced PEV at unlinked genes (5). In this model, gene products act as a ''source'' of heterochromatin forming potential, and DNA sequences destined to be heterochromatic as a ''sink.'' A balance is normally maintained between gene products and target DNA in the genome, although no proposed mechanism satisfactorily accounts for how this balance is maintained during division, determination, and differe...

Epigenetic effects of polymorphic Y chromosomes modulate chromatin components, immune response, and sexual conflict

“…It was recently reported that variable rDNA array size contributes to variation in PEV phenotype when examined in isolation (35). However, when naturally occurring Y chromosome lines with different rDNA array sizes are probed, PEV phenotypes can be opposite of that expected based on their rDNA size alone.…”

Ribosomal DNA copy number is coupled with gene expression variation and mitochondrial abundance in humans

“…Recent data suggested that rDNA deletions might disrupt GE levels and chromatin states in Drosophila 8,23 . Substantial association in dosage among unlinked loci further lends support to the hypothesis that variability at the rDNA loci might have functional relevance for GE states across the genome.…”

Formation of nuclear heterochromatin

“…In this case, rDNA deletions result in reduced heterochromatin-induced gene silencing elsewhere in the genome and the extent of the rDNA deletion correlates with the loss of silencing. 23 Taken together, the data described so far suggest that the analysis of the components of silent rDNA chromatin has the potential to provide novel insights into the formation of nuclear heterochromatic H4K20me3) are all found at silent CpG methylated rRNA repeats, 14,15 underscoring the crosstalk between DNA methylation and histone marks. Similarly, histone modifications that associate with gene activity (H4Ac, H3K4me2) are features of active rRNA genes.…”