Organisation and function of the Nucleolar Organiser Regions in human chromosomes.
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The short-arms of the five acrocentric human chromosomes contain sequences that direct the assembly and function of the nucleolus, one of the key functional domains of the nucleus and ribosomal biogenesis, yet they are absent from the human genome assembly. It is well known that not all 10 NORs are active in the cells but the regulatory mechanisms that regulate their activity have not been identified. Previous reports, suggested that a chromatin remodeling factor, BAZ2A, is a nucleolar protein that plays a role in rDNA silencing and could be implicated in whole NOR inactivation. I have tested this hypothesis and found no evidence in support of it. Instead I focused on describing the genomic architecture of the human NORs. This was driven by the hypothesis that sequences outwith the rDNA could regulate NOR activity. Sequences found distally and proximally to ribosomal gene arrays were found to be conserved among the acrocentric chromosomes and to share a complex genomic architecture similar to other euchromatic regions of the genome. However, they have distinct genomic characteristics. Proximal sequences are almost entirely segmentally duplicated. In contrast, the distal sequence is predominantly unique to the acrocentric short arms, and is dominated by a large inverted repeat. This distal element was found to localize to the periphery of the nucleolus, where it appears to anchor the ribosomal gene repeats. This combined with its complex chromatin structure and production of transcripts that behave like lncRNAs, localizing to their site of synthesis, suggests that this region is involved in nucleolar organization. Further work on these novel genetic elements will shed light on the well-known empirical association of altered nucleolar morphology and function with human pathology.