Ribosomal RNA (rRNA) gene transcription accounts for most of the RNA in prokaryotic and eukaryotic cells. Nucleolus organizer regions (NORs), which span millions of base pairs, include hundreds to thousands of tandemly repeated head-to-tail rRNA genes in eukaryotes. RNA Polymerase I (Pol I) transcribes these nucleolar rRNA genes, and the expression of these genes is regulated by the physiological requirement for ribosomes. Regulation occurs at several levels, one of which is an epigenetic on/off switch that controls the number of active rRNA genes. Additional mechanisms then fine-tune transcription initiation and elongation rates to dictate the total amount of rRNA produced per gene. In this review, we focus on the DNA and histone modifications that comprise the epigenetic on/off switch. In both plants and animals, this system is important for controlling the dosage of active rRNA genes. The dosage control system is also responsible for the chromatin-mediated silencing of one parental set of rRNA genes in genetic hybrids, a large-scale epigenetic phenomenon known as nucleolar dominance. First described in interspecific plant hybrids and allopolyploids, nucleolar dominance has become a valuable model for understanding RNA-guided chromatin regulation and epigenetic gene silencing. Rather than arising from differences in DNA sequence, nucleolar dominance is established and maintained through coordinated interactions between chromatin remodeling, DNA methylation, histone modifications, and diverse classes of non-coding RNAs. In plants, the RNA-directed DNA methylation (RdDM) pathway, involving RNA Polymerases IV and V, Dicer-like proteins, Argonaute proteins, and 24-nucleotide small interfering RNAs (siRNAs), plays a central role in directing sequence-specific DNA methylation and heterochromatin formation at inactive ribosomal DNA (rDNA) loci. These RNA-mediated pathways function together with ATP-dependent chromatin-remodeling complexes, histone deacetylases, and DNA methyltransferases to establish stable transcriptional repression. In mammals, although classical nucleolar dominance is uncommon, selective silencing of subsets of rRNA genes is regulated through promoter-associated RNAs (pRNAs), long non-coding RNAs, the Nucleolar Remodeling Complex (NoRC), and epigenetic modifications that determine the balance between active and inactive rDNA repeats. Collectively, these mechanisms ensure appropriate ribosome biogenesis, preserve genome integrity, maintain nucleolar organization, and enable cellular adaptation to developmental and environmental cues.
