Abstract
The spatial organization of the genome is enigmatic. Direct evidence of physical contacts between chromosomes and their visualization at nanoscale resolution has been limited. We used superresolution microscopy to demonstrate that ribosomal DNA (rDNA) can form linkages between chromosomes. We observed rDNA linkages in many different human cell types and demonstrated their resolution in anaphase. rDNA linkages are coated by the transcription factor UBF and their formation depends on UBF, indicating that they regularly occur between transcriptionally active loci. Overexpression of c-Myc increases rDNA transcription and the frequency of rDNA linkages, further suggesting that their formation depends on active transcription. Linkages persist in the absence of cohesion, but inhibition of topoisomerase II prevents their resolution in anaphase. We propose that linkages are topological intertwines occurring between transcriptionally active rDNA loci spatially colocated in the same nucleolar compartment. Our findings suggest that active DNA loci engage in physical interchromosomal connections that are an integral and pervasive feature of genome organization.
Highlights
The human genome is packaged into 23 pairs of chromosomes that occupy distinct territories in the nucleus and can form interchromosomal contacts (Cremer et al, 1993; Bolzer et al, 2005; Meaburn and Misteli, 2007)
Linkages between ribosomal DNA (rDNA) regions of acrocentric chromosomes are ubiquitous in human cells We used conventional microscopy and superresolution microscopy (SIM) to study chromatin organization of the rDNA. rDNA repeats were directly labeled by FISH using rDNA probes labeled with fluorescent dyes
Chromosome spreads from human mammary epithelial cells (HMECs) imaged by wide-field microscopy revealed physical connections between acrocentric chromosomes at the rDNA loci (Fig. 1 C, left panel, arrows 1–3)
Summary
The human genome is packaged into 23 pairs of chromosomes that occupy distinct territories in the nucleus and can form interchromosomal contacts (Cremer et al, 1993; Bolzer et al, 2005; Meaburn and Misteli, 2007). 45S genes in the human genome are present in several hundred nearly identical copies (Scherer, 2008); their actual number varies among individuals (Gibbons et al, 2015; Xu et al, 2017a). The 45S ribosomal DNA (rDNA) genes present a potential paradigm of interchromosomal interactions because they are present on multiple chromosomes that regularly associate together in interphase nuclei to form the nucleolus (McStay, 2016). They are organized in tandem repeats that are partitioned among the short arms of five acrocentric chromosome pairs: 13, 14, 15, 21, and 22 (Henderson et al, 1972; Fig. 1 A). Each rDNA repeat unit consists of the coding region producing the transcript to be processed into 28S, 5.8S, and 18S rRNAs and a long noncoding intergenic spacer (Fig. 1 B)
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