\"Transcriptional regulation is one of the most important processes for modulati
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Question
"Transcriptional regulation is one of the most important processes for modulating gene expression. Though much of this control is attributed to transcription factors, histones, and associated enzymes, it is increasingly apparent that the spatial organization of chromosomes within the nucleus has a profound effect on transcriptional activity. Studies in yeast indicate that the nuclear pore complex might promote transcription by recruiting chromatin to the nuclear periphery. In higher eukaryotes, however, it is not known whether such regulation has global significance. Here we establish nucleoporins as a major class of global regulators for gene expression in Drosophila melanogaster. Using chromatin-immunoprecipitation combined with microarray hybridization, we show that Nup153 and Megator (Mtor) bind to 25% of the genome in continuous domains extending 10 kb to 500 kb. These Nucleoporin-Associated Regions (NARs) are dominated by markers for active transcription, including high RNA polymerase II occupancy and histone H4K16 acetylation. RNAi-mediated knock-down of Nup153 alters the expression of approximately 5,700 genes, with a pronounced down-regulatory effect within NARs. We find that nucleoporins play a central role in coordinating dosage compensation-an organism-wide process involving the doubling of expression of the male X chromosome. NARs are enriched on the male X chromosome and occupy 75% of this chromosome. Furthermore, Nup153-depletion abolishes the normal function of the male-specific dosage compensation complex. Finally, by extensive 3D imaging, we demonstrate that NARs contribute to gene expression control irrespective of their sub-nuclear localization. Therefore, we suggest that NAR-binding is used for chromosomal organization that enables gene expression control." --Vaquerizas et al. (2010). PLoS Genet. 6(2):e1000846.
The RNAi knockdown experiments show that the nucleoporins typically promote or inhibit transcription in the NARs? Briefly explain.
Compare and contrast dosage compensation in Drosophila melanogaster to dosage compensation in humans
Explanation / Answer
Q1. RNAi (RNA interference) is a molecular technique of down-regulating (knocking-down) of specific genes at the post-transcriptional level. This is achieved by introducing small non-coding RNAs, called miRNAs (Micro-RNAs), complementary to the transcript of the gene of interest. They bind to the specific transcript, resulting the activation of RNAi pathway, which cleaves the transcript, so as to block the translation of the mRNA.
In the context of the paragraph, the authors knocked down the transcript of the nucleoporin gene Nup153, which resulted in either upregulation or inhibition of many NAR-specific gene. This indicates that, Nup153 regulates many NAR-specific genes.
Q2. Dosage compensation is a mechanism to compensate the expression levels of the genes of the sex-chromosomes. This is necessary, as there are unequal number of sex chromosomes (for example, XY in human males and XX in females) in both the sexes. In case of humans, the genes of X chromosomes will be doubled in females otherwise, without dosage compensation.
In humans, dosage compensation is achieved by randomly inactivating of one of the X chromosomes in females, to compensate the extra copies of the genes on the second X-chromosome. In Drosophila, it is achieved by the doubling of the expression of genes on the single X-chromosome in males.
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