Reaching for the off switch in nucleolar dominance.

Nucleolus organizer regions (NORs) are eukaryotic chromosomal loci where ribosomal RNA (rRNA) genes are clustered, typically in hundreds to thousands of copies. Transcription of these rRNA genes by RNA polymerase I and processing of their transcripts results in the formation of the nucleolus, the sub-nuclear domain in which ribosomes are assembled. Approximately 90 years ago, cytogenetic observations revealed that NORs inherited from the different parents of an interspecific hybrid sometimes differ in morphology at metaphase. Fifty years ago, those chromosomal differences were found to correlate with differences in rRNA gene transcription and the phenomenon became known as nucleolar dominance. Studies of the past 30 years have revealed that nucleolar dominance results from selective rRNA gene silencing, involving repressive chromatin modifications, and occurs in pure species as well as hybrids. Recent evidence also indicates that silencing depends on the NOR in which an rRNA gene is located, and not on the gene's sequence. In this perspective, we discuss how our thinking about nucleolar dominance has shifted over time from the kilobase scale of individual genes to the megabase scale of NORs and chromosomes and questions that remain unanswered in the search for a genetic and biochemical understanding of the off switch. © 2023 Society for Experimental Biology and John Wiley & Sons Ltd.