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Epigenetic Regulation of the X-Chromosomal Macrosatellite Repeat Encoding for the Cancer/Testis Gene CT47

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Epigenetic Regulation of the X-Chromosomal Macrosatellite Repeat Encoding for the Cancer/Testis Gene CT47 European Journal of Human Genetics (2012) 20, 185–191 & 2012 Macmillan Publishers Limited All rights reserved 1018-4813/12 www.nature.com/ejhg ARTICLE Epigenetic regulation of the X-chromosomal macrosatellite repeat encoding for the cancer/testis gene CT47 Judit Balog1, Dan Miller2, Elena Sanchez-Curtailles1, Jose Carbo-Marques1, Gregory Block2, Marco Potman1, Peter de Knijff1, Richard JLF Lemmers1, Stephen J Tapscott3 and Silve`re M van der Maarel*,1 Macrosatellite repeats (MSRs) present an extreme example of copy number variation, yet their epigenetic regulation in normal and malignant cells is largely understudied. The CT47 cancer/testis antigen located on human Xq24 is organized as an array of 4.8 kb large units. CT47 is expressed in the testis and in certain types of cancer, but not in non-malignant somatic tissue. We used CT47 as a model to study a possible correlation between copy number variation, epigenetic regulation and transcription originating from MSRs in normal and malignant cells. In lymphoblastoid cell lines and primary fibroblasts, CT47 expression was absent, consistent with the observed heterochromatic structure and DNA hypermethylation of the CT47 promoter. Heterochromatinization of CT47 occurs early during development as human embryonic stem cells show high levels of DNA methylation and repressive chromatin modifications in the absence of CT47 expression. In small-cell lung carcinoma cell lines with low levels of CT47 transcripts, we observed reduced levels of histone 3 lysine 9 trimethylation (H3K9me3) and trimethylated lysine 27 of histone H3 (H3K27me3) without concomitant increase in euchromatic histone modifications. DNA methylation levels in the promoter region of CT47 are also significantly reduced in these cells. This supports a model in which during oncogenic transformation, there is a relative loss of repressive chromatin markers resulting in leaky expression of CT47. We conclude that some MSRs, like CT47 and the autosomal MSRs TAF11-Like, PRR20, ZAV and D4Z4, the latter being involved in facioscapulohumeral muscular dystrophy, seem to be governed by common regulatory mechanisms with their abundant expression mostly being restricted to the germ line. European Journal of Human Genetics (2012) 20, 185–191; doi:10.1038/ejhg.2011.150; published online 3 August 2011 Keywords: macrosatellite repeats; cancer/testis antigen; copy number variation; epigenetics; D4Z4; FSHD INTRODUCTION (FSHD).1,5 Other MSRs that have been studied in various details Approximately half of the human genome is composed of repetitive include DXZ4 on the X chromosome, which was recently proposed to DNA and a significant proportion of this DNA is arranged as have a role in X-chromosome inactivation;3 RS447, which encodes for tandemly repeated units. It is now widely accepted that these elements a deubiquitinating enzyme;6 and RNU2, encoding a small nuclear are an integral part of the genome with structural and regulatory RNA,7 TAF11-Like,8,9 which was recently suggested to be involved in a functionalities. Macrosatellite repeats (MSRs) are a specific class of psychiatric disorder, and very recently SST1, PRR20 and ZAV.9 repeated DNA defined by a minimum unit size of 100 bp. Typically, D4Z4 is characterized by bidirectional transcriptional activity, high MSR unit sizes are much larger and MSRs usually span hundreds of DNA methylation and the presence of both heterochromatic histone kilobases of DNA. MSRs can be protein-coding or non-coding, and modifications such as histone 3 lysine 9 trimethylation (H3K9me3) as are often subtelomerically or centromerically located. MSRs have been well as the transcriptionally permissive histone modification such implicated to be involved in human disease,1 including cancer,2 and as dimethylated lysine 4 of histone H3 (H3K4me2). Upon contraction, epigenetic regulation of the genome, such as X inactivation.3 Recently, as seen in FSHD, D4Z4 becomes hypomethylated,10 shows selective loss a genome-wide survey revealed that MSRs are more abundant than of H3K9me3, with secondary losses of heterochromatin protein 1g and previously anticipated, are distributed over the entire genome and are the cohesin complex,11 thus leading to a more open chromatin organized in a higher order structure.4 Owing to their size variability, structure. DXZ4 has chromatin features very similar to D4Z4, but MSRs thus represent an important source of copy number variation shows opposite chromatin configurations on the active (Xa) and (CNV) that may contribute to the missing heritability observed in inactive (Xi) X chromosome. On Xa, DXZ4 is organized as constitutive some genome-wide association and CNV studies. heterochromatin with high levels of H3K9me3, while on the Xi, DXZ4 The structure and function of MSRs is largely understudied. adopts a more euchromatic structure with high levels of H3K4me2 and Probably the best studied MSR is D4Z4, because contractions of H3K9ac. Also, DXZ4 is bidirectionally transcribed with discrete differ- this MSR are associated with facioscapulohumeral muscular dystrophy ences in the transcriptional landscape on Xa and Xi.3 1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 2Department of Pediatrics, University of Washington, Seattle, WA, USA; 3Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA *Correspondence: Professor SM van der Maarel, Department of Human Genetics, Leiden University Medical Center, PO Box 9600, Leiden AL 2333, The Netherlands. Tel: +31 71 526 9480; Fax: +31 71 526 8285; E-mail: [email protected] Received 8 February 2011; revised 5 July 2011; accepted 6 July 2011; published online 3 August 2011 Epigenetic regulation of CT47 macrosatellite JBaloget al 186 From these studies, the picture emerges that CNV, expression profile Xq24 and chromatin structures are important attributes of MSRs, which when Chromosome X disturbed may have consequences for genome integrity and function, as has recently been demonstrated in Saccharomyces cerevisiae where large Number of CT47 units 4-17 rDNA repeats are required for the maintenance of genome integrity.12 Cancer/testis antigens (CTAs) represent a class of genes that are 119,893,246 119,948,579 typically only expressed in germ cells of the testis, fetal ovary and CT47 array placenta, and sometimes in the brain, and which also show expression in 4.8 kb various tumor types.13,14 Epigenetic changes in cancer typically involve hypermethylation of CpG islands and hypomethylation of repetitive CT47 transcript 15,16 A B DNA elements. Hypermethylation can lead to transcriptional silen- CD cing of tumor suppressor genes while the effect of hypomethylation in Figure 1 Schematic representation of CT47 macrosatellite array. The CT47 cancer is less clear, but thought to contribute to genomic instability. In repeat array is localized on Xq24 at coordinates chrX: 119 893 246– accordance, it has been established that many CTAs show expression in 119 948 579 according to hg18 assembly. The size of the array varies malignancies, which is associated with promoter demethylation.17,18 between 4 and 17 units, each unit being 4.8 kb in size. Chromatin markers However, by and large, the chromatin structure of CTAs under normal were studied in the promoter region of the CT47 gene encoded by each unit and malignant conditions has not been studied in great detail. (exons are indicated in gray boxes). Genomic locations where relative The cancer/testis gene CT47 on Xq24 is arranged as an MSR with abundance of different histone modifications were quantified are represented by the black line; A represents ChIP primer set for CT47 promoter, B up to 17 copies of a putative protein coding gene ordered head to represents distal primer set located 3.7 kb from the array, C represents ChIP 19 tail. Being a CTA and an MSR, in this study we set out to examine primer set for CT47 exon 3, and D represents the bisulfate primer set. the array length and chromatin structure of this MSR in CT47- expressing and -non-expressing cells. against H3K4me2 (no. 07-030), H3K9me3 (no. 17-625) and trimethylated lysine 27 of histone H3 (H3K27me3) (no. 17-622) were purchased from MATERIALS AND METHODS Millipore (Billerica, MA, USA). EZH2 antibody was purchased from Active Cell lines and culturing conditions Motif (no. 39103) and the histone H3 antibody (La Hulpe, Belgium; HapMap cell lines and primary fetal lung fibroblast WI38 were purchased from no. ab1791) from Abcam (Cambridge, UK). Coriell Cell Repositories (Camden, NJ, USA) and cultured according to the To determine the level of nonspecific signals, we used IgG, which was supplier’s instruction. Small-cell lung carcinoma (SCLC) cell lines were supplied with the antibodies for H3K9me3 and H3K27me3. Immunoprecipita- purchased from LGC Standards GmbH (LGC Promochem, Teddington, UK) tion with histone antibodies and IgG was carried out with a chromatin and cultured as described;20 human embryonic stem cells (hESCs) WA9 and containing 3 mg DNA. Immunoprecipitation with EZH2 antibody and IgG WA14 21 were purchased from WiCell Research Institute (Madison, WI, USA). was carried out with a chromatin containing 6 mg DNA. The amount of Cells were cultured according to a published protocol.22 hESC and human immunopurified DNA was determined by quantitative PCR with specific embryonic body (hEB) samples were analyzed for the presence of the primer pairs at three different sites in CT47: promoter primer pair (labeled differentiation markers NANOG, OCT4 and XIST as described,23 and showed A in Figure 1), exon 3 primer pair (labeled C in Figure 1) and distal primer pair that ESCs had differentiated properly. (labeled D in Figure 1). All primers were designed by primer3 program and optimized for minimizing sequence variations between individual repeat units. Primers were tested for specificity on a monochromosomal cell panel. A Primers published primer pair was used for the GAPDH promoter.26 Relative abun- All primers used in the study are described in Supplementary Table S1. dance of histone modifications was calculated in the following way: enrichment values obtained with IgG were subtracted from the enrichment values from Characterization of the CT47 array specific antibodies.
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