Ribosomal RNA (rRNA) genes are organized in tandem arrays known as ribosomal DNA (rDNA) on multiple chromosomes in Hominidae genomes. We measured copy number and transcriptional activity status of rRNA gene arrays across multiple individual genomes, revealing an identifiable fingerprint of rDNA copy number and activity. In some cases, entire arrays were transcriptionally silent, characterized by high DNA methylation across the rRNA gene, inaccessible chromatin, and the absence of transcription factors and transcripts. Silent arrays showed reduced association with the nucleolus and decreased interchromosomal interactions, consistent with the model that nucleolar organizer function depends on transcriptional activity. Removing rDNA methylation activated silent arrays. Array activity status remained stable through induced pluripotent stem cell reprogramming and differentiation into cerebral and intestinal organoids. Haplotype tracing in two unrelated family trios showed paternal transmission of silent arrays. We propose that the epigenetic state buffers rRNA gene dosage, specifies nucleolar organizer function, and can propagate transgenerationally.

Department of Genetics Genomics and Informatics University of Tennessee Health Science Center Memphis TN USA

Genome Informatics Section Center for Genomics and Data Science Research National Human Genome Research Institute National Institutes of Health Bethesda MD USA

Masaryk University Brno Czech Republic

Stowers Institute for Medical Research Kansas City MO USA

Stowers Institute for Medical Research Kansas City MO USA; Department of Biochemistry and Molecular Biology University of Kansas Medical Center Kansas City KS USA

UC Santa Cruz Genomics Institute University of California Santa Cruz Santa Cruz CA USA

Wellcome Sanger Institute Hinxton Cambridge UK

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