Satellite DNA and related diseases

Satellite DNA, also known as tandemly repeated DNA, consists of clusters of repeated sequences and represents a diverse class of highly repetitive elements. Satellite DNA can be divided into several classes according to the size of an individual repeat: microsatellites, minisatellites, midisatellite...

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Datum:	2014
Hauptverfasser:	Rich, J., Ogryzko, V.V., Pirozhkova, I.V.
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spelling	nasplib_isofts_kiev_ua-123456789-1544332025-02-09T13:35:45Z Satellite DNA and related diseases Сателітна ДНК і пов’язані хвороби Сателлитная ДНК и сопутствующие заболевания Rich, J. Ogryzko, V.V. Pirozhkova, I.V. Reviews Satellite DNA, also known as tandemly repeated DNA, consists of clusters of repeated sequences and represents a diverse class of highly repetitive elements. Satellite DNA can be divided into several classes according to the size of an individual repeat: microsatellites, minisatellites, midisatellites, and macrosatellites. Originally considered as «junk» DNA, satellite DNA has more recently been reconsidered as having various functions. Moreover, due to the repetitive nature of the composing elements, their presence in the genome is associated with high frequency mutations, epigenetic changes and modifications in gene expression patterns, with a potential to lead to human disease. Therefore, the satellite DNA study will be beneficial for developing a treatment of satellite-related diseases, such as FSHD, neurological, developmental disorders and cancers. Сателітна ДНК, також відома як тандемно повторювана ДНК, складається з кластерів повторюваних послідовностей, об’єднаних у широкий клас часто повторюваних елементів. Сателітнi ДНК можна розділити на декілька класів залежно від розміру ок- ремого повтора: мікросателітні, мінісателітні, мідісателітні і макросателітні ДНК. Сателітну ДНК спочатку розглядали як «сміттєву». Лише зовсім недавно таку концепцію було переглянуто і наразі сателітну ДНК відносять до ДНК, якій притаманні різні функції. Крім того, присутність у геномі повторюваних послідовностей пов’язана з високою частотою мутацій, епігенетичними змінами і модифікаціями в профілі експресії генів, що потенційно може призвести до різних патологій. Таким чином, вивчення сателітної ДНК буде корисним при розробці терапії, спрямованої на лікування захворювань, пов’язаних iз сателітною ДНК, таких як м’язова дистрофія FSHD, неврологічні патології, хвороби, обумовлені порушеннями розвитку, та онкологічні захворювання. Сателлитная ДНК, также известная как тандемно повторяющаяся ДНК, состоит из кластеров повторяющихся последовательностей, объединенных в широкий класс часто повторяющихся элементов. Сателлитную ДНК можно разделить на несколько классов в зависимости от размера отдельного повтора: микросателлитная, минисателлитная, мидисателлитная и макросателлитная ДНК. Сателлитную ДНК первоначально рассматривали как «мусорную». Только совсем недавно эта концепция была пересмотрена, в результате чего сателлитную ДНК относят к ДНК, обладающей различными функциями. Кроме того, присутствие в геноме повторяющихся последовательностей связано с высокой частотой мутаций, эпигенетическими изменениями и модификациями в профиле экспрессии генов, что потенциально может привести к различным патологиям. Таким образом, изучение сателлитной ДНК будет полезно при разработке терапии, направленной на лечение заболеваний, таких как мышечная дистрофия FSHD, неврологические патологии, болезни, обусловленные нарушениями развития, и онкологические заболевания. 2014 Article Satellite DNA and related diseases / J. Rich, V.V. Ogryzko, I.V. Pirozhkova // Вiopolymers and Cell. — 2014. — Т. 30, № 4. — С. 249-259. — Бібліогр.: 112 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00089E https://nasplib.isofts.kiev.ua/handle/123456789/154433 577.21 + 616.00 en Вiopolymers and Cell application/pdf Інститут молекулярної біології і генетики НАН України
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
language	English
topic	Reviews Reviews
spellingShingle	Reviews Reviews Rich, J. Ogryzko, V.V. Pirozhkova, I.V. Satellite DNA and related diseases Вiopolymers and Cell
description	Satellite DNA, also known as tandemly repeated DNA, consists of clusters of repeated sequences and represents a diverse class of highly repetitive elements. Satellite DNA can be divided into several classes according to the size of an individual repeat: microsatellites, minisatellites, midisatellites, and macrosatellites. Originally considered as «junk» DNA, satellite DNA has more recently been reconsidered as having various functions. Moreover, due to the repetitive nature of the composing elements, their presence in the genome is associated with high frequency mutations, epigenetic changes and modifications in gene expression patterns, with a potential to lead to human disease. Therefore, the satellite DNA study will be beneficial for developing a treatment of satellite-related diseases, such as FSHD, neurological, developmental disorders and cancers.
format	Article
author	Rich, J. Ogryzko, V.V. Pirozhkova, I.V.
author_facet	Rich, J. Ogryzko, V.V. Pirozhkova, I.V.
author_sort	Rich, J.
title	Satellite DNA and related diseases
title_short	Satellite DNA and related diseases
title_full	Satellite DNA and related diseases
title_fullStr	Satellite DNA and related diseases
title_full_unstemmed	Satellite DNA and related diseases
title_sort	satellite dna and related diseases
publisher	Інститут молекулярної біології і генетики НАН України
publishDate	2014
topic_facet	Reviews
url	https://nasplib.isofts.kiev.ua/handle/123456789/154433
citation_txt	Satellite DNA and related diseases / J. Rich, V.V. Ogryzko, I.V. Pirozhkova // Вiopolymers and Cell. — 2014. — Т. 30, № 4. — С. 249-259. — Бібліогр.: 112 назв. — англ.
series	Вiopolymers and Cell
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fulltext	REVIEWS UDC 577.21 + 616.00 Satellite DNA and related diseases J. Rich, V. V. Ogryzko, I. V. Pirozhkova CNRS, University Paris 11; UMR8126: Nuclei & Innovations in Oncology, Gustave-Roussy 114, rue Edouard Vaillant, Villejuif Cedex, 94805 iryna.pirozhkova@gustaveroussy.fr Satellite DNA, also known as tandemly repeated DNA, consists of clusters of repeated sequences and represents a diverse class of highly repetitive elements. Satellite DNA can be divided into several classes according to the size of an individual repeat: microsatellites, minisatellites, midisatellites, and macrosatellites. Originally consi- dered as «junk» DNA, satellite DNA has more recently been reconsidered as having various functions. More- over, due to the repetitive nature of the composing elements, their presence in the genome is associated with high frequency mutations, epigenetic changes and modifications in gene expression patterns, with a potential to lead to human disease. Therefore, the satellite DNA study will be beneficial for developing a treatment of satellite- related diseases, such as FSHD, neurological, developmental disorders and cancers. Keywords: satellite DNA, repeated sequences, frequency mutations, satellite-related diseases. The non-coding DNA – is it «junk» or functional? Only a tiny percentage of human DNA is coding for pro- teins, whereas the non-coding DNA, transposons and transposon-derived elements make up the majority of the genome [1]. This fact was first discovered already in the 70’s of the last century. Later, the efforts of the Human Genome Project resulted in the estimation of the percentage of non-coding DNA of the human genome as 98–99 %. This somewhat surprising fact led Susumi Ohno to suggest the notion of «junk DNA», referring to the idea that most genomic DNA has no use for the organism [2]. According to Richard Dawkins, one of the leaders of the pro-«Junk» concept, «the greater part of the geno- me might as well not be there, for all the difference it makes» [3]. This claim found support in recent work showing that the megabase sized deletion of non-coding sequences in mice has no phenotypic effect [4]. There were, indeed, good reasons (based on the mathematical population genetics), to expect that most of the sequen- ces in a typical eukaryotic genome (except only about 30000 loci, according to Ohno) could not be under se- lection, and thus could not be important. The concept of «junk DNA» was also supported by the so-called C-va- lue enigma, according to which the genome size does not correlate with the complexity level of the organism [5] – e. g., humans have genomes much smaller than those of some single cell eukaryotes. However, with the completion of the Human Ge- nome Project and the launching of the ENCODE (The Encyclopedia of DNA Elements) project by the US Na- tional Human Genome Research Institute (NHGRI), the prevailing view that portrays most of the human geno- me as having no function whatsoever, has become less and less sustainable. The ENCODE project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These da- ta allowed researchers to assign the biochemical func- tions for 80 % of the human genome, in particular to non- coding regions, highlighting an evidence of the functio- nality of non-protein-coding DNA. One of the demon- strations is the transcription of most non-protein- coding DNA into RNA [6]. Only 4 % of the 65000 RNAs produced by genome are coming from exons [7]. It would not make sense for the organism to waste pre- 249 ISSN 0233–7657. Biopolymers and Cell. 2014. Vol. 30. N 4. P. 249–259 doi: http://dx.doi.org/10.7124/bc.00089E � Institute of Molecular Biology and Genetics, NAS of Ukraine, 2014 250 cious resources transcribing such DNA, if it were not functional. Moreover, hundreds of non-coding regions of DNA have been recently found to be 100 % conser- ved between humans and mice (called ultra-conserved elements, UCEs) [8]. The perfect conservation of these regions makes an argument for their evolutionary im- portance. Much further evidence of functionality of non-pro- tein-coding DNA has been shown. For example, the in- trons regulating an alternative splicing [9–12] are in- volved in gene expression [5, 13, 14] and chromatin or- ganization [15, 16], some pseudogenes are involved in lipid metabolism [17], in the process of protein synthe- sis [18], and in the RNA interference [19, 20]. The changes in our views on the functional impor- tance of non-coding DNA also concern the «poster child» of the junk DNA concept – the so called satellite DNA, the main subject of this review. Satellite DNA in genome organization. In humans, recent estimations based on the results of the Human Genome project suggest that about 70 % of the genome is represented by repetitive and repeat-derived DNA elements [21]. The repeated sequences can be divided into two categories (Fig. 1): – The «interspersed repeated sequences», when the repeating copies are dispersed over the genome. – The «tandem repeated sequences» (also called satellite DNA), when the repeating copies are adjacent to each other. Satellite DNA is a diverse class of highly repetitive units, accounting for approximately 10–15 % of all re- petitive DNA sequences in the human genome [22]. The size of one tandem repeat unit can vary dramatical- ly, i. e., from one base pair (bp) to several hundred bps. According to the orientation of the repeat units in tan- dem, two types of repeats can be distinguished: i) direct repeats, which are head-to-tail orientated and ii) inver- ted repeats, which are head-to-head orientated. How- ever, only direct repeats are frequently found in geno- mes, whereas the inverted repeats are rare, presumably because they can induce double strand breaks [23]. First thought as an artefact, satellite DNA was dis- covered in 1961, as additional peaks appeared during fractionation of DNA according to floating density in gradient of caesium salts [24, 25]. Ten years later, the enrichment of highly repetitive satellite DNA in the constitutive heterochromatin regions was described [26]. Satellite DNA can be located in different parts of chromosomes with the preference in telomeric and cent- romeric regions. The examples of satellite DNA are the telomeres, the centromeres and the ribosomal genes. Despite numerous studies, the functional significance of satellite DNA is still poorly understood. Classification of satellite DNA. Satellite DNA is divided into several categories according to size, struc- ture and localization. However, a universally accepted classification does not exist so far, and the scheme can vary among authors [23, 27, 28]. According to the size of an individual repeat, satellite DNA can be divided in- RICH J. ET AL. Genome Repeated DNA Extragenic DNA Unique or low copy number DNA Interspersed repeats Transposons LINE SINE LTR Minisatellites Microsatellites Midisatellites Macrosatellites Introns, untranslated sequences Tandem repeats Protein coding DNA Genes and gene- related sequences Non-protein coding DNA Pseudogenes Gene fragments Fig. 1. Organization of eukaryotic genome to four classes: (1) microsatellites (less than 10 bp per repeat), (2) minisatellites (10–60 bp per repeat), (3) sa- tellites (up to hundreds of bp per repeat) and (4) macro- satellites (several kb per repeat). To avoid potential con- fusion, we propose naming the third class of satellite repeats as midisatellites, leaving the term of «satellite DNA» to encompass all tandemly repeated DNA. The most abundant human satellites are the simp- lest repeats (microsatellites), which are also called sim- ple sequence repeats (SSR), or short tandem repeats (STR) in the literature. These repeats are widely spread in plant and animal genomes; for example, there is, on average, one microsatellite every 2 kb in the human ge- nome [29]. The microsatellites are frequently involved in neurodegenerative diseases caused by the strong ex- pansion of SSR in one gene [30]. One of their main cha- racteristics is a high rate of instability manifested in a loss or gain of repeat units, which is explained by i) the non-homologous recombination between homologous chromosomes and ii) the replication errors [31]. The microsatellites have been shown to emerge as ubiqui- tous genetic markers for many eukaryotic genomes [32– 34]. This could be useful in the evolutionary studies re- garding the genetic relationships. The minisatellites exhibit some similarities with the sequence of lambda-phage (GCTGTGG) and the majo- rity of them are GC-rich with a strong strand asymmet- ry. Among others, this class of satellite tandem DNA contains the hypermutable repeats, which are flanked by DSB (double-strand break) hot spots and show a high rate of meiotic instability. Because of their length poly- morphism, the minisatellites are used for DNA finger- printing in forensic science for the identification of individuals by their respective DNA profiles. In addi- tion, they have been proposed to serve as markers for ge- notoxicity [35]. Very little is known about the midisatellite non-co- ding DNA, which is mostly located in the telomeric or centromeric regions of chromosomes. This kind of sa- tellite DNA is represented by �, � and �-satellite re- peats. Alpha-satellite repeats (ASR), composed of a tan- dem array of a 171 bp repeat unit, are located at the cent- romeres of all human chromosomes. ASR play a cru- cial role in the chromosome segregation of normal and human artificial chromosomes (HACs) [36]. The beta- satellite DNA was described by Waye and Willard, and is presented by tandem arrays of divergent Sau3A 67– 69 pb monomer repeat units [37]. Beta satellite repeats (BSR) show a predominant heterochromatic distribu- tion, which includes the short arm of acrocentric chro- mosomes and the pericentomeric part of chromosomes 1, 3 and 9 [38, 39]. In these regions, beta satellite arrays are adjacent to LSau 3.3 kb macrosatellites (D4Z4-like repeats). The D4Z4 macrosatellite repeats and BSR are also located in the subtelomeric regions of chromoso- mes 4 and 10 [40, 41]. Recently, the presence of BSR next to a newly created telomere has been shown to re- tard its replication timing [42]. The DNA of gamma- satellite repeats (GSR), a tandem array of 220-bp GC- rich repeating units, was identified in the pericentro- meric regions of human chromosomes 8, X, and Y. GSR usually form 10–200 kb clusters, flanked by alpha-sa- tellite DNA. It has been proposed that the primary role of the gamma-satellite DNA is to prevent the pericent- romeric genes from epigenetic silencing [43]. The macrosatellite repeat (MSR) DNA is the only satellite DNA that could contain an open reading frame (ORF) and thus, could produce protein-coding RNA in every repeat unit, as illustrated by the D4Z4 (DUX4), CT47, RS447, TAF11-Like and PRR20 repeats. In com- parison to the telomeric or centromeric satellites, which could be present on many chromosomes, MSR are often specific for only one or two chromosomes. Additional- ly, MSR are mostly expressed in the germ lines, with the expression being affected by the methylation status of DNA. Moreover, MSR could be associated with both transcriptionally active and silenced chromatin [28, 44]. Other non-coding MSR, such as DXZ4, have been shown to play a mechanical role, and are involved in the formation of MSR chromatin topology [45]. The role of MSR is not well known. Therefore, D4Z4 is probably one of the most studied macrosatellites because of its as- sociation with facioscapulohumeral muscular dystro- phy (FSHD). Clinical relevance of satellite DNA. In recent years, much attention has been brought to the role of repeat se- quences in various pathologies, such as epilepsy, emb- ryonic lethality and cancers [46, 47]. The increase in the number of copies of repeats in genomic DNA is the single most important cause of nearly 30 hereditary di- sorders [48]: the X-fragile syndrome [49], the myoto- nic dystrophy [50], the Huntington’s disease [51], the 251 SATELLITE DNA AND RELATED DISEASES Friedreich’s ataxia [52], etc. Scott et al. have described the first evidence of the insertion of 18 beta-satellite units in to the gene coding transmembraine serine pro- tease resulting in autosomal recessive deafness [53]. Most of these diseases are due to the microsatelli- tes, whose structural features often result in the disrup- tion of DNA replication, repair and recombination pro- cesses, leading to expanded or contracted DNA structu- res. The microsatellite expansion has been implicated in serious myopathies, as well as in neuromuscular and neurodegenerative hereditary diseases. The majority of the disorders are caused by the expansion of the triplet repeats (CGG)(CCG), (CAG)(CTG), (GAA)(TTC) and (GCN)(NGC). Nevertheless, diseases can also re- sult from the expansion of a tetranucleotide, a pentanuc- leotide and even a dodecanucleotide repeat [48]. The microsatellite expansion diseases can result in a gain or/and loss of function. Among disorders caused by gain-of-function mechanism, the main cause is the protein conformation alteration, leading to changes in protein activity or abundance. As an example, the poly- glutamine diseases, one of the nine classes of gain-of- function disorders, are due to the expansion of CAG re- peat. These include Huntington disease (HD), Kennedy disease and Spinocerebellar ataxia (SCA) [54, 55]. Af- fected individuals develop nuclear inclusion bodies con- taining aggregated proteins with expanded polygluta- mine stretches. Alternatively, the repression of the gene transcrip- tion, caused by the microsatellite expansion, leads to the loss-of-function mechanism. For example, fragile X mental retardation 1 gene (FMR1) is associated with (CGG)n satellite expansion, resulting in the transcrip- tion silencing and the loss of FMRP, the protein pro- duct of FMR1 gene [56]. Other examples of loss of pro- tein expression are Jacobsen syndrome [57] and Fried- reich’s ataxia [58]. The contributions of the micro- satellite expansion could be manifested by both gain and loss of function mechanisms as it has been demonst- rated for spinocerebellar ataxia type 1 (SCA1) [59]. Intriguingly, for the microsatellite-expansion rela- ted pathologies, a correlation has been reported bet- ween the size of the repeat tandem and the severity of the disease [60]. This correlation is behind the phenome- non of genetic anticipation, according to which the pro- gressive increase in the repeat number (to be inherited in subsequent generations) results in the increased seve- rity and earlier manifestation of disease [61]. Impor- tantly, the expandable microsatellite repeats responsib- le for a particular disease are usually located within the affected gene, in either the coding (ORF) or else the non- coding (promoters, introns and UTRs) regions of it [47]. In the cases other than microsatellites, the exact mo- lecular mechanisms of how satellite DNA can be invol- ved in pathology remain largely unexplored, particu- larly when satellite DNA is not located in the coding re- gion of the affected gene. Among the unresolved issues are: (i) the relative role of satellite DNA presence and (ii) the contribution of genetic and epigenetic factors, i. e., whether structural modifications (tandem size, nuc- leotide sequence etc.) of satellite DNA provide the star- ting point, or the epigenetic modifications play the pri- mary role in the mechanism of pathology. The slow pro- gress in this matter could be explained by the metho- dological difficulties in studying large repeating DNA sequences, as well as by the lack of animal models that could replicate the symptoms of the hereditary satelli- te-related diseases in humans. Cancer as a satellite-related disease. «Breaking of satellites’ silence» is now a new paradigm in canceroge- nesis [62]. While gene-specific loci can be either hypo- or hypermethylated in cancer, the highly repeated DNA sequences are only hypomethylated in this disease. Mo- reover, the global DNA hypomethylation observed so frequently in cancers is mostly due to satellite DNA. Ehrlich et al. were the first to demonstrate the hypome- thylation of tandem minisatellite centromeric DNA (na- mely centromere-adjacent satellite 2, (Sat2)) in breast adenocarcinomas [63], ovarian epithelial tumors [64] and Wilms tumors [65]. A highly significant difference in the methylation level was found in satellite repeats (SATR1 and ARLa) in neurosarcoma [66]. In 76 % of hepatocellular carcinoma cases, the reduction in Sat2 methylation has also been demonstrated [67]. More recently, Zhu et al. showed that the loss of the BRCA1 tumour suppressor gene provoked satellite-DNA de- repression in breast and ovarian tumours of mice and humans [68]. Satellite DNA hypomethylation has been postulated as the mechanism that underlies the induc- tion of peri-centromeric instability in many human can- cers [69]. All together, these results suggest satellite re- peats to be the main target for hypomethylation. 252 RICH J. ET AL. Recently, a 40 fold-increase of the ASR tandem se- quence expression has been observed for cancers of lung, kidney, ovary, colon, and prostate. More impressi- vely, a 131-fold increase of the pericentromeric satelli- te Sat2 transcripts has been demonstrated in pancreatic tumors in comparison with normal pancreases [70]. Interestingly, other satellites, such as BSR, GSATII and TARI were not affected. However, some tandem repeats, NBL2 and D4Z4, could be hypomethylated in some cancers and hyperme- thylated in others, which could be explained by de novo methylation processes [71, 72]. There is no data in the literature concerning the po- tential mechanisms for the selective demethylation of satellite DNA in cancer. Nevertheless, this phenome- non and the overexpression of satellite transcripts in this disease could potentially be useful as a biomarker for cancer detection and for the evaluation of the effica- cy of anti-cancer treatment. In addition, epigenetic can- cer therapy directed against global methylation chan- ges needs to be reconsidered towards the targeting of the only affected DNA, in order to avoid side effects. The knowledge of what satellite DNA is implicated in particular cancer will be important in cancer study. One can expect that the search for links between sa- tellite DNA, tumor suppressors and genomic instability promises new routes for cancer therapy. However, the molecular connections between the satellite hypome- thylation and the cancer development remain obscure. The opening of chromatin at satellite repeat regions re- sulting in the mislocalization of the transcription machi- nery, could lead to the aberrations in gene regulation with pathological consequences [73]. Additional me- chanism explaining the changes in transcriptional re- gulation may be achieved through the remodelling and looping of chromatin [74, 75], as described in our dis- cussion of FSHD below, or through the involvement of long-noncoding RNA (lncRNA) [76]. It has been shown that repeating sequences can massively produce lncRNA, which can further contribute to the epigenetic changes leading to pathology [70, 77, 78]. In every type of can- cer analyzed so far, at least 200 lncRNA have been found to be affected [79]. Among those lncRNA, some important validated candidates for prognostic indica- tors and/or functionally relevant universal «drivers» and «suppressors» of drug-resistant metastasis have been identified [80]. One can expect that these figures will in- crease in the near future, thanks to the efforts of the ENCODE project in decrypting 98 % of non-protein- coding DNA of the human genome, including satellite DNA, which aim is to characterize the non-coding trans- criptional landscape and to analyze the possible expres- sion of extremely short peptides encoded by lncRNA [81]. The role of satellite DNA in cancer illustrates again that, whereas it was first introduced as «junk» DNA, in fact it plays an important role in genome functioning. Moreover, there are suggestions in the literature that the purifying selection, responsible for the conserva- tion of the DNA satellite sequences in evolution, is due to the oncological consequences of the mutations in satellite DNA [82]. Facioscapulohumeral muscular dystrophy as a satellite-related disease. Another example of clinical relevance of satellite DNA is the FSHD disease, which is associated with the macrosatellite (D4Z4) and beta-sa- tellite (4qA allele) DNA sequences. It is an autosomal dominant muscular dystrophy ranking second after Du- chenne muscular dystrophy, with an incidence of 1: 14,000 throughout the world (2010, The FSH Society). FSHD is clinically characterized by a progressive mus- cular weakness in an up-to-down manner involving face, pectoral girdle, upper limbs, lower limbs and hips [83, 84]. The FSHD locus was mapped in the 1990s by linka- ge analysis in the subtelomeric region of the long arm of chromosome 4 (4q35) [85–87]. The causal molecu- lar anomaly is the contraction of the macrosatellite tandem size consisting of D4Z4 repeats. In the normal population, the number of copies is polymorphic and varies from 11 to 150. In 90–95 % of the FSHD pati- ents, this number is decreased to 1–10 units [88]. The lower the repeat number, the younger the age of the be- ginning of the disease and the higher the severity of the disease [89]. The presence of at least one D4Z4 repeat is necessary to develop the disease, as patients with 4qter deletion have no FSHD symptoms [90]. D4Z4 is a macrosatellite repeat of 3303 bp length (Fig. 2). Each unit contains LSau and hhspm3 inter- spersed repeats and an open reading frame of 1173 bp, named DUX4, which contains two homeobox domains [91, 92]. LSau is a Long Sau3A-repeated element of 253 SATELLITE DNA AND RELATED DISEASES 340 bp, whereas hhspm3 (a human DNA insert showing sperm-specific hypomethylation Sp-0.3-8) is a GC-rich low copy repeat sequence of 467 bp. The open reading frame has neither introns nor a polyadenylation site in the D4Z4 repeat unit and is preceded by a promoter (box TACAA) located 149 bp upstream [93]. DBE (D4Z4 Binding Element), located 181 bp upstream of DUX4, is a binding site for the YY1 transcriptional re- pressor, HMGB2 (High-Mobility Group Protein B2) and nucleolin and was shown to be responsible for epi- genetic repression [94, 95]. In addition, the presence of a strong enhancer was demonstrated in each D4Z4 re- peat [96]. Both the transcriptional repressor DBE and the transcriptional activator were shown to mediate the transcriptional control of 4q35 genes. The 4qter and 10qter regions possess 99 % of homo- logy, which extends over more than 200 kb [97]. The 10qter located repeats can be distinguished by the pre- sence of a Blnl restriction site [97]. There is a repeat ex- change between 10qter and 4qter regions in 20 to 30 % of the population [98], which creates 4q/10q hybrid se- quences. FSHD is specific to chromosome 4 because the contraction in 10q26 is not associated with the disease. The second satellite DNA sequence associated with FSHD is a BSR tandem of 6.2 kb length (4qA allele) in 4q35 locus downstream of D4Z4 [40]. The 4qA allele is present in about half of a normal population. In contrast to the 4qA, the 4qB allele does not contain the BSR tan- dem and the reduction of D4Z4 MSR tandem does not result in the manifestation of the disease. Evolutionary analysis by Van Geel et al. indicates that the 4qA allele is older than the 4qB [99]. Moreover, evolution-wise, FSHD appears as a very young disease, present only in humans, as the linked D4Z4-BSR clusters from the FSHD region were found only in chimpanzees, and even this primate has never been found to suffer from FSHD [100]. The FSHD-like, or FSHD2, type of the disease re- presents 5 % of FSHD and is characterised by the high frequency of sporadic cases (70 %) and the absence of macrosatellite contraction in 4q. Nevertheless, the pre- sence of the BSR 4qA allele remains a necessary con- dition for FSHD2 development [101]. Recently, we ha- ve demonstrated that the BSR fragment from the 4qA allele possesses the properties of a transcriptional acti- vator [102]. These observations strongly suggest the significance of the BSR presence in FSHD develop- ment. Macrosatellites can provoke epigenetic changes. Chromatin. First studies showed that the D4Z4 macrosa- tellite has in most cases the features of «unexpressed eu- chromatin» [103]. Some specific changes in post-trans- lational modifications (PTM) of histones in FSHD we- re described [104]. In healthy individuals, D4Z4 has both the heterochromatic (trimethylation of H3K9 and H3K27) and euchromatic marks (dimethylation of H3K4 and acetylation of H3). The FSHD patients present a loss of H3K9 trimethylation in both chromosomes 4q and 10q. In addition to the changes in histone PTMs, several studies demonstrated that the reduced number of D4Z4 macrosatellite repeats in FSHD myoblasts was associa- 254 RICH J. ET AL. Fig. 2. Structure of 4q35 locus and D4Z4 repeat. Each 3303 bp repeat is flanked by KpnI sites and contains following regions: LSau; hhspm3; DBE and DUX4 ORF (positioned, respectively 1–340 bp, 1313–1780 bp, 1584–1611 bp and 1792–3063 bp from the 5' KpnI site) [91, 92, 94]. The positions of two cis-elements: an activator [96] and an insulator [105] are also indicated (1–170 bp and 460– 1197 bp). Here, DBE (D4Z4 Bin- ding Element), BSR (beta-satellite repeat), ANT1 (Adenine Nucleotide Translocator gene1), FRG1/2 (FSHD Region Gene 1/2) ted with a global alteration of the chromatin organiza- tion in the 4q35 region [74, 75]. Moreover, our work has provided evidence about the potential role of the 4qA BSR marker in chromatin remodeling in FSHD (Fig. 3) [102]. These results have been obtained by the Chromo- some Conformation Capture (3C) methodology, which evaluates the spatial proximity of two given genomic fragments based upon their relative propensity to be li- gated in vitro. Later on, Ottavini et al. showed that the D4Z4 mac- rosatellite repeat acts as a CTCF insulator protecting the adjacent genes, activated in pathology, from their hete- rochromatization in FSHD patients (Fig. 2) [105]. The loss of this feature was observed with the increase of the number of D4Z4 repeat units. This is an example of how a change in tandem repeat copy number (i) leads to a switch of its function from repressor to insulator and (ii) provokes dramatic downstream biological effects. DNA methylation. The significant hypomethylation of D4Z4 CpG dinucleotides was observed in FSHD1 patients compared with the healthy individuals [106]. FSHD1 patients show hypomethylation in the contrac- ted D4Z4 allele, with the methylation degree depen- ding on the number of repeats. In particular, the hypo- methylation is more significant in the patients with short D4Z4 tandem (3–6 repeat units) than in the patients with moderate size of MSR (6–9 repeat units). This obser- vation suggests a correlation between the severity of di- sease, the number of D4Z4 repeats and their methyla- tion level [107]. On the other hand, hypomethylation might contribute to the disease independent of contrac- tion, as the FSHD2 patients without a decrease in the number of D4Z4 repeat units also present a strong hypo- methylation of the satellite on chromosomes 4q and 10q [106, 108]. In both cases (FSHD1 and FSHD2), the hypomethylation takes place in the macrosatellite re- gion (D4Z4) and does not extend to the adjacent region towards centromere. Nothing is known about the methy- lation status of the adjacent region extending towards telomere. The D4Z4 hypomethylation may provide the mis- sing link between DNA changes and transcriptional de- repression in FSHD. Whatever the exact nature of this mechanism is, the D4Z4 hypomethylation in FSHD in- dividuals strongly supports a central role of epigenetic events in the pathogenic pathway of FSHD. Satellite DNA: therapeutic targets? Several publi- cations have highlighted the existence of crosstalk bet- ween the MSR DUX4 expression and the differentia- tion state of cells. The MSR gene is expressed in germ line and embryonic cells and is epigenetically repres- sed in somatic cells [44, 109]. In FSHD patients, it has been proposed that the DUX4 transcript is transiently expressed at a pre-myoblast stage in the affected re- gions of skeletal muscles and possibly among certain subsets of muscle satellite cells. This could result (i) in the upregulation of the expression of adjacent genes and (ii) in the dampening of the expression of many muscle lineage-associated genes, during regenerative myogenesis. This, in turn, could decrease the efficien- cy of the late stages of regenerative myogenesis or af- fect the muscle function in a manner consistent with the usually slow progression of FSHD. Recently, another mechanism of the MSR DUX4 expression has been proposed. It consists in the expres- sion of a DUX4 full length stable RNA, which is trans- cribed from the last unit of D4Z4, which includes the 3'UTR region containing two facultative introns and a 255 SATELLITE DNA AND RELATED DISEASES Fig. 3. Architecture of 4q35 FSHD locus. The reduction of macrosatelli- te tandem provokes the drastic chan- ges in chromatin organization. The 3C analysis of chromatin organiza- tion of control (left) and FSHD (right) myoblasts [102] polyadenylation site. The canonical polyadenylation si- te is only present in the pLAM sequence associated with BSR of the 4qA allele [41, 93]. This long DUX4 trans- cript was found in half of examining biopsies samples from FSHD patients. Additionally, the high level of this long DUX4 transcript was observed in special pools of muscle cells representing 0.1 % of FSHD culturing mus- cles [110]. According to these two models of FSHD development, DUX4 expression is considered as the main therapeutic target for FSHD. Further on, Dixit and collaborators reported that, in the muscles of FSHD patients, the transcription of DUX4 was associated with an increase of a homeodomain transcription factor PITX1 [93]. They showed that the DUX4 protein can act as a transcriptional activator of PITX1. Another study showed the existence of partial transcripts of small RNAs (mi/siRNA) resulting from DUX4 [109]. These findings provide additional thera- peutic targets for FSHD. More recently, however, the DUX4-centric paradigm of FSHD development has been challenged. The inap- propriate expression of the DUX4 stable transcript that takes place in FSHD pathogenesis was observed in FSHD fibroblasts [110], which are not affected in FSHD, as well as in muscles and myogenic cells of some unaf- fected individuals without D4Z4 deletion [111]. These somewhat controversial observations suggest that the ro- le of DUX4 expression in FSHD and its potential role as a therapeutic target require a more thorough exploration. As far as the second satellite repeat (BSR) actor in the FSHD development is concerned, little is known about the functional role of the 4qA allele. Previously, we have shown that a 1.5 kbp fragment from 4qA allele contains a transcriptional activator [102], allowing us (i) to suggest that the presence of BSR could influence the transcriptional activation of adjacent or juxtaposed sequences and (ii) to propose that the protein activator of 4qA would be a new therapeutic target for FSHD. Altogether, the recent progress in the studies of FSHD, including our own data, suggests that the speci- fic satellite DNA, macrosatellite (D4Z4) and beta-satel- lite (4qA) sequences are essential for the development of this disease and could be considered as potential targets for the gene therapy in FSHD treatment. Conclusions. Much experimental evidence review- ed in this manuscript, indicates that the study of satelli- te DNA promises to provide important insights into hu- man diseases, as they are related to transcription cont- rol and often have an impact on chromatin structure and genomic instability [112]. Despite many technical chal- lenges due to their repeated nature, the manipulation of satellite DNA might have great therapeutic potential in the treatment of FSHD, neurological, developmental dis- orders and cancers. These arguments warrant further investigations on various mechanisms regarding satelli- te DNA functions in the genome. Acknowledgements. We thank Mr. R. Willett (CNRS) for the copy editing. Ñàòåë³òíà ÄÍÊ ³ ïîâ’ÿçàí³ õâîðîáè Æ. Ð³÷, Â. Â. Îãðèçüêî , ². Â. Ï³ðîæêîâà Ðåçþìå Ñàòåë³òíà ÄÍÊ, òàêîæ â³äîìà ÿê òàíäåìíî ïîâòîðþâàíà ÄÍÊ, ñêëàäàºòüñÿ ç êëàñòåð³â ïîâòîðþâàíèõ ïîñë³äîâíîñòåé, îá’ºäíà- íèõ ó øèðîêèé êëàñ ÷àñòî ïîâòîðþâàíèõ åëåìåíò³â. Ñàòåë³òíi ÄÍÊ ìîæíà ðîçä³ëèòè íà äåê³ëüêà êëàñ³â çàëåæíî â³ä ðîçì³ðó îê- ðåìîãî ïîâòîðà: ì³êðîñàòåë³òí³, ì³í³ñàòåë³òí³, ì³ä³ñàòåë³òí³ ³ ìàêðîñàòåë³òí³ ÄÍÊ. Ñàòåë³òíó ÄÍÊ ñïî÷àòêó ðîçãëÿäàëè ÿê «ñì³òòºâó». Ëèøå çîâñ³ì íåäàâíî òàêó êîíöåïö³þ áóëî ïåðåãëÿ- íóòî ³ íàðàç³ ñàòåë³òíó ÄÍÊ â³äíîñÿòü äî ÄÍÊ, ÿê³é ïðèòàìàíí³ ð³çí³ ôóíêö³¿. Êð³ì òîãî, ïðèñóòí³ñòü ó ãåíîì³ ïîâòîðþâàíèõ ïî- ñë³äîâíîñòåé ïîâ’ÿçàíà ç âèñîêîþ ÷àñòîòîþ ìóòàö³é, åï³ãåíå- òè÷íèìè çì³íàìè ³ ìîäèô³êàö³ÿìè â ïðîô³ë³ åêñïðåñ³¿ ãåí³â, ùî ïîòåíö³éíî ìîæå ïðèçâåñòè äî ð³çíèõ ïàòîëîã³é. Òàêèì ÷èíîì, âèâ÷åííÿ ñàòåë³òíî¿ ÄÍÊ áóäå êîðèñíèì ïðè ðîçðîáö³ òåðàï³¿, ñïðÿìîâàíî¿ íà ë³êóâàííÿ çàõâîðþâàíü, ïîâ’ÿçàíèõ iç ñàòåë³òíîþ ÄÍÊ, òàêèõ ÿê ì’ÿçîâà äèñòðîô³ÿ FSHD, íåâðîëîã³÷í³ ïàòîëîã³¿, õâîðîáè, îáóìîâëåí³ ïîðóøåííÿìè ðîçâèòêó, òà îíêîëîã³÷í³ çà- õâîðþâàííÿ. Êëþ÷îâ³ ñëîâà: ñàòåë³òíà ÄÍÊ, ïîâòîðþâàí³ ïîñë³äîâíîñò³, ÷àñòîòà ìóòàö³é, çàõâîðþâàííÿ, ïîâ’ÿçàí³ ³ç ñàòåë³òíîþ ÄÍÊ. Ñàòåëëèòíàÿ ÄÍÊ è ñîïóòñòâóþùèå çàáîëåâàíèÿ Æ. Ðè÷, Â. Â. Îãðûçüêî, È. Â. Ïèðîæêîâà Ðåçþìå Ñàòåëëèòíàÿ ÄÍÊ, òàêæå èçâåñòíàÿ êàê òàíäåìíî ïîâòîðÿþ- ùàÿñÿ ÄÍÊ, ñîñòîèò èç êëàñòåðîâ ïîâòîðÿþùèõñÿ ïîñëåäîâà- òåëüíîñòåé, îáúåäèíåííûõ â øèðîêèé êëàññ ÷àñòî ïîâòîðÿþ- ùèõñÿ ýëåìåíòîâ. Ñàòåëëèòíóþ ÄÍÊ ìîæíî ðàçäåëèòü íà íå- ñêîëüêî êëàññîâ â çàâèñèìîñòè îò ðàçìåðà îòäåëüíîãî ïîâòîðà: ìèêðîñàòåëëèòíàÿ, ìèíèñàòåëëèòíàÿ, ìèäèñàòåëëèòíàÿ è ìàê- ðîñàòåëëèòíàÿ ÄÍÊ. Ñàòåëëèòíóþ ÄÍÊ ïåðâîíà÷àëüíî ðàñ- ñìàòðèâàëè êàê «ìóñîðíóþ». Òîëüêî ñîâñåì íåäàâíî ýòà êîíöåï- öèÿ áûëà ïåðåñìîòðåíà, â ðåçóëüòàòå ÷åãî ñàòåëëèòíóþ ÄÍÊ îò- íîñÿò ê ÄÍÊ, îáëàäàþùåé ðàçëè÷íûìè ôóíêöèÿìè. Êðîìå òîãî, ïðèñóòñòâèå â ãåíîìå ïîâòîðÿþùèõñÿ ïîñëåäîâàòåëüíîñòåé ñâÿ- çàíî ñ âûñîêîé ÷àñòîòîé ìóòàöèé, ýïèãåíåòè÷åñêèìè èçìåíåíè- ÿìè è ìîäèôèêàöèÿìè â ïðîôèëå ýêñïðåññèè ãåíîâ, ÷òî ïîòåíöè- àëüíî ìîæåò ïðèâåñòè ê ðàçëè÷íûì ïàòîëîãèÿì. Òàêèì îáðàçîì, èçó÷åíèå ñàòåëëèòíîé ÄÍÊ áóäåò ïîëåçíî ïðè ðàçðàáîòêå òåðà- 256 RICH J. 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Repetitive sequ- ences in complex genomes: structure and evolution. Annu Rev Genomics Hum Genet. 2007;8:241–59. Received 02.04.14 259 SATELLITE DNA AND RELATED DISEASES

Satellite DNA and related diseases

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