Abstract
The regions of the genome that interact frequently with the nucleolus have been termed nucleolar-associated domains (NADs). Deep sequencing and DNA-fluorescence in situ hybridization (FISH) experiments have revealed that these domains are enriched for repetitive elements, regions of the inactive X chromosome (Xi), and several RNA polymerase III-transcribed genes. NADs are often marked by chromatin modifications characteristic of heterochromatin, including H3K27me3, H3K9me3, and H4K20me3, and artificial targeting of genes to this area is correlated with reduced expression. It has therefore been hypothesized that NAD localization to the nucleolar periphery contributes to the establishment and/or maintenance of heterochromatic silencing. Recently published studies from several multicellular eukaryotes have begun to reveal the trans-acting factors involved in NAD localization, including the insulator protein CCCTC-binding factor (CTCF), chromatin assembly factor (CAF)-1 subunit p150, several nucleolar proteins, and two long non-coding RNAs (lncRNAs). The mechanisms by which these factors coordinate with one another in regulating NAD localization and/or silencing are still unknown. This review will summarize recently published studies, discuss where additional research is required, and speculate about the mechanistic and functional implications of genome organization around the nucleolus.
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Acknowledgments
This study was funded by the NIH R01 GM055712. We thank Dr. Thoru Pederson for the helpful review of this manuscript.
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Three-Dimensional Rendering of HeLa S3 Nucleus with and without CAF-1 p150 Depletion. Video 1 shows a HeLa S3 nucleus after 72 hours of expression of a control shRNA directed against luciferase. DAPI staining is in blue (A), the nucleolar and Cajal body protein Nopp140 in green (B) and the ribosomal rDNA in red (C). Video 2 shows a HeLa S3 nucleus after 72 hours of expression of an shRNA directed against CAF-1 p150 with the same channels as in Video 1. Note that Nopp140 does not localize to the nucleolus in video 2C, but does maintain localization to two different Cajal bodies. In contrast, the morphology of the nucleolus visualized by rDNA hybridization is not significantly different. (Methods, probes, and antibodies described in (Smith et al. 2014). The Nopp140 antibody (RS8) was a generous gift of U. Thomas Meier, Albert Einstein College of Medicine, New York, NY (Kittur et al. 2007). Z-stack images were taken on a Leica TCS SP5 II Laser Scanning Confocal Microscope and videos were generated using the Leica Application Suite AF version 2.5.1.6757) (AVI 71282 kb)
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Matheson, T.D., Kaufman, P.D. Grabbing the genome by the NADs. Chromosoma 125, 361–371 (2016). https://doi.org/10.1007/s00412-015-0527-8
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DOI: https://doi.org/10.1007/s00412-015-0527-8