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Effects of Human Sex Chromosome Dosage on Spatial Chromosome Organization

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Effects of Human Sex Chromosome Dosage on Spatial Chromosome Organization M BoC | ARTICLE Effects of human sex chromosome dosage on spatial chromosome organization Ziad Jowhara, Sigal Shachara, Prabhakar R. Gudlab, Darawalee Wangsac, Erin Torresd, Jill L. Russd, Gianluca Pegorarob, Thomas Riedc, Armin Raznahand,*, and Tom Mistelia,* aCell Biology of Genomes Group, bHigh-Throughput Imaging Facility, cGenetics Branch, National Cancer Institute, and dHuman Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892 ABSTRACT Sex chromosome aneuploidies (SCAs) are common genetic syndromes character- Monitoring Editor ized by the presence of an aberrant number of X and Y chromosomes due to meiotic defects. Rong Li These conditions impact the structure and function of diverse tissues, but the proximal effects Johns Hopkins University of SCAs on genome organization are unknown. Here, to determine the consequences of Received: Jun 13, 2018 SCAs on global genome organization, we have analyzed multiple architectural features of Revised: Jul 25, 2018 chromosome organization in a comprehensive set of primary cells from SCA patients with Accepted: Aug 1, 2018 various ratios of X and Y chromosomes by use of imaging-based high-throughput chromo- some territory mapping (HiCTMap). We find that X chromosome supernumeracy does not affect the size, volume, or nuclear position of the Y chromosome or an autosomal chromo- some. In contrast, the active X chromosome undergoes architectural changes as a function of increasing X copy number as measured by a decrease in size and an increase in circularity, which is indicative of chromatin compaction. In Y chromosome supernumeracy, Y chromo- some size is reduced suggesting higher chromatin condensation. The radial positioning of chromosomes is unaffected in SCA karyotypes. Taken together, these observations document changes in genome architecture in response to alterations in sex chromosome numbers and point to trans-effects of dosage compensation on chromosome organization. INTRODUCTION Sex chromosome aneuploidies (SCAs) are a class of genetic human (prevalence 2.5/1000) and associated with neurological, endocrine, syndromes that arise by the presence of an aberrant number of X immune, and metabolic phenotypes (Nielsen and Wohlert, 1991; and/or Y chromosomes beyond the typical XX for females and XY Linden et al., 1995; Bojesen et al., 2003; Goswami et al., 2003; for males (Disteche, 2012). Commonly studied SCAs include Turner Simpson et al., 2003; Stochholm et al., 2006; Chen et al., 2012; Link syndrome (X-monosomy in females [XO]) and Klinefelter syndrome, et al., 2013; Seminog et al., 2015; Mankiw et al., 2017). The down- which arises due to the presence of a supernumerary X chromosome stream phenotypic consequences of SCAs presumably arise from in males (XXY karyotype); other variations include XYY, XXX, the impact of atypical sex chromosome counts on genome function, and XXYY syndromes. These conditions are collectively common but genomic features of SCA remain poorly understood in humans (Bermejo-Alvarez et al., 2010; Arnold, 2012; Hughes and Rozen, 2012; Belling et al., 2017). This article was published online ahead of print in MBoC in Press (http://www To maintain cellular function, dosage compensation between .molbiolcell.org/cgi/doi/10.1091/mbc.E18-06-0359) on August 9, 2018. males and females in mammals is normally achieved by silencing *Address correspondence to: Armin Raznahan ([email protected]) or Tom Misteli ([email protected]). most of the genes in one of the two X chromosomes through a Abbreviations used: CTs, chromosome territories; DAPI, 4′,6-diamidino-2-phenyl- mechanism known as X chromosome inactivation (XCI), thus gener- indole; HiCTMap, high-throughput chromosome territory mapping; SCAs, ating two functionally different X chromosomes, the inactive X (Xi) sex chromosome aneuploidies; Xa, active X chromosome; XCI, X chromosome inactivation; Xi, inactive X chromosome. and active X (Xa; Clemson et al., 1996; Avner and Heard, 2001). The © 2018 Jowhar et al. This article is distributed by The American Society for Cell initiation of XCI requires the noncoding Xist (X-inactive-specific tran- Biology under license from the author(s). Two months after publication it is avail- script) RNA, a 17-kb-long untranslated transcript, which decorates able to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). Xi territories in cis (Brown et al., 1991; Clemson et al., 1996). Xist “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of recruits various chromatin-modifying factors that induce heterochro- the Cell®” are registered trademarks of The American Society for Cell Biology. matinization of the X chromosome, including histone methylation 2458 | Z. Jowhar et al. Molecular Biology of the Cell (i.e., H3K27me3) and deacetylation (H4 hypoacetylation) via PRC1/2 Karyotype Set number Sex Age (yr) and histone deacetylases (HDACs), respectively, repressive histones (macroH2A), and incorporation of DNA methylation (CpG islands) XO 1 F 21 by various DNA methyltransferases (DNMTs; Plath et al., 2002; de XX 1 F 22 Napoles et al., 2004; Chaumeil et al., 2006; Engreitz et al., 2013). XXX 1 F 14 To date, few studies have directly examined X inactivation in tis- sues from humans with SCA. A recent microarray study of lympho- XXXX 1 F 24 blastoid cell lines of a range of SCA karyotypes found that Xist XXXXY 1 M 16 activity increased sharply with increasing X-chromosome dosage, XXY 1 M 16 suggesting that the X-inactivation program is initiated for each ad- ditional X chromosome (Raznahan et al., 2018). Furthermore, ex- XXYY 1 M 21 pression of X-linked genes that are known to escape X inactivation XY 1 M 17 was positively correlated with X-chromosome dosage in SCAs, indi- XYY 1 M 24 cating that the phenomenon of escape is also maintained during XO 2 F 13 inactivation of the supernumerary X chromosomes in SCA. How- ever, the higher X-chromosome count across SCAs appears to be XX 2 F 18 associated with a sublinear increase in expression of escapees, and XXX 2 F 14 a derepresssion of X-linked genes that are subject to X inactivation XXXX 2 F 11 (i.e., expression greater in XO than XXX). Thus, current studies of gene expression in SCAs suggest that supernumerary X chromo- XXXXY 2 M 13 somes are inactivated, but that additional regulatory mechanisms XXY 2 M 19 may be operating to shape expression from both the active X chro- XXYY 2 M 12 mosome and the inactive X chromosome(s). Given the presence of extra copies of sex chromosomes in SCAs, XY 2 M 8 an unresolved question is whether the abnormal number of sex XYY 2 M 21 chromosomes leads to changes in the organization or spatial loca- XO 3 F 14 tion of chromosomes within the nucleus. Chromosomes are spatially confined to discreet nuclear volumes, each referred to as chromo- XX 3 F 17 some territory (CT; Schardin et al., 1985; Cremer et al., 1993; Kurz XXX 3 F 16 et al., 1996; Meaburn and Misteli, 2007) and they have characteris- XXXX 3 F 12 tic, heterogeneous, but nonrandom distributions within the three- dimensional space of the nucleus (Borden and Manuelidis, 1988; XXXXY 3 M 16 Croft et al., 1999; Bartova et al., 2002; Parada et al., 2004a,b; Misteli, XXY 3 M 16 2007). Interestingly, the Xi forms a distinct, condensed and spherical XXYY 3 M 13 structure (Barr body) and has a more peripheral position within the nucleus compared with the Xa chromosome (Chadwick and Willard, XY 3 M 25 2003; Bolzer et al., 2005; Teller et al., 2011). XYY 3 M 19 In this study, we take advantage of a unique, comprehensive set Description of patient-derived skin fibroblast cells used for experiments. of cells from individuals with various SCAs including XO, XXX, XXXX, Karyotypes, sex, and ages are indicated. Cells were obtained by skin punch XXY, XYY, XXYY, and XXXXY (Table 1) to probe the effects of sex biopsy. chromosome supernumeracy on chromosome organization. Our TABLE 1: Primary skin fibroblast cells: description and origin. studies are enabled by the recent development of HiCTMap, a 384- well plate–based chromosome paint fluorescence in situ hybridiza- tion (FISH) imaging method (Jowhar et al., 2018) to characterize the based imaging method that allows systematic, high-resolution im- size, shape, and positioning of chromosomes in large numbers of aging of thousands of nuclei in hundreds of samples and it can cells at high throughput. We find that in SCAs, the X chromosome accurately measure structural features of chromosomes such as undergoes architectural changes as a function of X copy number size, shape, and spatial position at the single chromosome level indicated by a decrease in size and increase in circularity, suggesting (Jowhar et al., 2018). We applied this pipeline to a comprehensive chromatin compaction. Similarly, the Y chromosome decreases in set of patient-derived primary cells that were acquired via skin bi- size as a function of Y copy number. All chromosomes studied main- opsy from seven SCA patients (XO, XXX, XXXX, XXXXY, XXY, XXYY, tain canonical spatial positioning regardless of sex chromosome XYY) and normal male (XY) and female (XX) controls (Figure 1A and number. Our results provide insight into the structural consequences Table 1). Skin fibroblast cells from three patients per karyotype that of changes in genome organization induced by sex chromosome ranged from ages 8 to 25 were analyzed (Table 1). Cells were rou- supernumeracy. tinely cultured for no more than three to seven passages before analysis to minimize the possibility of genomic changes and their RESULTS stable karyotype was confirmed by spectral karyotyping (SKY; Detection and analysis of chromosome territories using unpublished data). Normal cell growth was verified using the HiCTMap in nuclei from SCA patients proliferation marker Ki-67 (Supplemental Figure S1) and normal To identify the effects of extra copies of either X and/or Y chromo- cell cycle profiles were observed at various cell densities (Supple- somes on spatial genome organization, we applied the previously mental Figure S2).
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