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Affinity publisher spread columns7/31/2023 ![]() In this study, we used Hi-C, a technique that enables the study of all chromosomal interactions within a genome at once ( Lieberman-Aiden et al., 2009). Current models are based on linear genomic analysis or DNA fluorescent in situ hybridization (DNA FISH) on few individual loci ( Grimaud and Becker, 2009) without accounting for the potential influence of global chromosome conformation. However, these features, although moderately enriched on the X, are also found on autosomes and thus it has not been possible to fully characterize HAS. The MSL complex preferentially binds to an active chromatin environment containing a consensus sequence motif, termed MSL recognition element (MRE), that is flanked by sequences of elevated GC content ( Alekseyenko et al., 2012 Conrad and Akhtar, 2012). Yet, how HAS are organized to allow the complex to reach the whole X chromosome continues to be an enigma. During this process, MOF acetylates histone H4 lysine 16 across the entire X chromosome, which ultimately upregulates transcription ( Conrad and Akhtar, 2012). The formation of this ribonucleoprotein complex is believed to occur at the roX gene loci as roX RNAs are the only components of the complex being produced within the nucleus.īased on both genetic and genomic analyses, the complex is thought to first target genomic regions called high-affinity sites (HAS), which include the roX genes, and then to spread to lower affinity sites. The MSL complex consists of four core proteins (MSL1, MSL2, MS元 and males absent on the first (MOF)) that together form a heterooctameric complex which is further stabilized by integration of two lncRNAs, called RNA on the X (roX) 1 and 2 by the ATP-dependent RNA helicase maleless (MLE) ( Keller and Akhtar, 2015). In Drosophila melanogaster, dosage compensation happens on the single male X chromosome by formation of the male-specific lethal (MSL) complex that promotes approximately 2-fold transcriptional upregulation ( Conrad and Akhtar, 2012). ![]() To overcome the risk of an unequal transcriptional output, different organisms have evolved independent strategies (termed “dosage compensation”) to balance the X chromosomal gene dose between the sexes ( Vicoso and Charlesworth, 2006): in mammals, expression of the long non-coding RNA (lncRNA) Xist from only one of the two female X chromosomes leads to recruitment of silencing complexes in cis, through which this chromosome becomes compacted and heterochromatinized ( Heard and Disteche, 2006). In the XX/XY sex determination system, males are heterogametic (XY) and females are homogametic (XX). Notably, the regulatory mechanisms of sex chromosomes offer ideal paradigms to understand how expression of an entire chromosome, and therefore thousands of genes at once, can be controlled by epigenetic mechanisms ( Brockdorff and Turner, 2015).ĭimorphic sex chromosomes genetically determine sex in many organisms. ![]() The organization of chromosomes within the nucleus and the spatial arrangement of genes within a chromosome territory are gaining fundamental importance during epigenetic control of gene expression ( Quinodoz and Guttman, 2014). We propose that sex-independent three-dimensional conformation of the X chromosome poises it for exploitation by the MSL complex, thereby facilitating spreading in males. We show that the MSL complex regulates nucleosome positioning at HAS, thus acting locally rather than influencing the overall chromosomal architecture. Ectopically expressed roX1 and roX2 RNA target HAS on the X chromosome in trans and, via spatial proximity, induce spreading of the MSL complex in cis, leading to increased expression of neighboring autosomal genes. By using Hi-C and 4C analyses we show that high-affinity sites (HAS), landing platforms of the male-specific lethal (MSL) complex, are enriched around topologically associating domain (TAD) boundaries on the X chromosome and harbor more long-range contacts in a sex-independent manner. ![]() Dosage compensation mechanisms provide a paradigm to study the contribution of chromosomal conformation towards targeting and spreading of epigenetic regulators over a specific chromosome. ![]()
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