A classical revival: Human satellite DNAs enter the genomics era

Altemose, Nicolas

doi:10.1016/j.semcdb.2022.04.012

Cited by 34 publications

(34 citation statements)

References 162 publications

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“…One of the main obstacles to the study of the functions of tandemly repeated satellite DNA was the lack of a complete map of the chromosome pericentromeric regions [ 20 ]. Until 2022, HSAT1–3 arrays in the human genome were not mapped precisely with their approximate locations in the genome assembly marked as enormous gaps filled with placeholder “N” characters [ 7 ]. The situation changed drastically when a new gapless genome assembly, CHM13-T2T, with fully assembled pericentromeres and centromeres, was published [ 21 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…The same GGAAT pentamer was the origin of human satellite 2 DNA (HSAT2, previously referred to as HS2). However, HSAT3 shows a strict periodicity of 5 bp, and HSAT2 is built on two tandemly repeated ATTCCATTCG and one or two ATG repeats with a consensus of 23 and 26 bp [ 3 , 4 , 7 ]. The GATGAT motif features HS3 of the 1qh region [ 8 ] (the band nomenclature is given according to the International System for Human Cytogenomic Nomenclature [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines

Ponomartsev

Zilov

Gushcha

et al. 2023

IJMS

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Pericentromeric tandemly repeated DNA of human satellites 1, 2, and 3 (HS1, HS2, and HS3) is actively transcribed in some cells. However, the functionality of the transcription remains obscure. Studies in this area have been hampered by the absence of a gapless genome assembly. The aim of our study was to map a transcript that we have previously described as HS2/HS3 on chromosomes using a newly published gapless genome assembly T2T-CHM13, and create a plasmid overexpressing the transcript to assess the influence of HS2/HS3 transcription on cancer cells. We report here that the sequence of the transcript is tandemly repeated on nine chromosomes (1, 2, 7, 9, 10, 16, 17, 22, and Y). A detailed analysis of its genomic localization and annotation in the T2T-CHM13 assembly revealed that the sequence belonged to HSAT2 (HS2) but not to the HS3 family of tandemly repeated DNA. The transcript was found on both strands of HSAT2 arrays. The overexpression of the HSAT2 transcript increased the transcription of the genes encoding the proteins involved in the epithelial-to-mesenchymal transition, EMT (SNAI1, ZEB1, and SNAI2), and the genes that mark cancer-associated fibroblasts (VIM, COL1A1, COL11A1, and ACTA2) in cancer cell lines A549 and HeLa. Co-transfection of the overexpression plasmid and antisense nucleotides eliminated the transcription of EMT genes observed after HSAT2 overexpression. Antisense oligonucleotides also decreased transcription of the EMT genes induced by tumor growth factor beta 1 (TGFβ1). Thus, our study suggests HSAT2 lncRNA transcribed from the pericentromeric tandemly repeated DNA is involved in EMT regulation in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines

Ponomartsev

Zilov

Gushcha

et al. 2023

IJMS

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“…Interestingly, the DNA constituting the secondary constriction of some satellited chromosomes, turns out to be due to repeat expansions, as in FRAXA, ICF, etc. New sequencing and bioinformatic tools are only beginning to harness a full appreciation of these tandem repeats and their relationship to chromosome structure ( Cechova, 2020 ; Liehr, 2021 ; Suzuki and Morishita, 2021 ; Thakur et al, 2021 ; Altemose, 2022 ; Altemose et al, 2022 ; Cechova and Miga, 2022 ; Gall-Duncan et al, 2022 ; Hoyt et al, 2022 ; Nurk et al, 2022 ). This nomenclature, while not comprehensive, lacks clear boundaries.…”

Section: Fragile Sites and Repeatsmentioning

confidence: 99%

Fragile sites, chromosomal lesions, tandem repeats, and disease

Mirceta

Shum²,

Schmidt³

et al. 2022

Front. Genet.

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Expanded tandem repeat DNAs are associated with various unusual chromosomal lesions, despiralizations, multi-branched inter-chromosomal associations, and fragile sites. Fragile sites cytogenetically manifest as localized gaps or discontinuities in chromosome structure and are an important genetic, biological, and health-related phenomena. Common fragile sites (∼230), present in most individuals, are induced by aphidicolin and can be associated with cancer; of the 27 molecularly-mapped common sites, none are associated with a particular DNA sequence motif. Rare fragile sites (≳ 40 known), ≤ 5% of the population (may be as few as a single individual), can be associated with neurodevelopmental disease. All 10 molecularly-mapped folate-sensitive fragile sites, the largest category of rare fragile sites, are caused by gene-specific CGG/CCG tandem repeat expansions that are aberrantly CpG methylated and include FRAXA, FRAXE, FRAXF, FRA2A, FRA7A, FRA10A, FRA11A, FRA11B, FRA12A, and FRA16A. The minisatellite-associated rare fragile sites, FRA10B, FRA16B, can be induced by AT-rich DNA-ligands or nucleotide analogs. Despiralized lesions and multi-branched inter-chromosomal associations at the heterochromatic satellite repeats of chromosomes 1, 9, 16 are inducible by de-methylating agents like 5-azadeoxycytidine and can spontaneously arise in patients with ICF syndrome (Immunodeficiency Centromeric instability and Facial anomalies) with mutations in genes regulating DNA methylation. ICF individuals have hypomethylated satellites I-III, alpha-satellites, and subtelomeric repeats. Ribosomal repeats and subtelomeric D4Z4 megasatellites/macrosatellites, are associated with chromosome location, fragility, and disease. Telomere repeats can also assume fragile sites. Dietary deficiencies of folate or vitamin B12, or drug insults are associated with megaloblastic and/or pernicious anemia, that display chromosomes with fragile sites. The recent discovery of many new tandem repeat expansion loci, with varied repeat motifs, where motif lengths can range from mono-nucleotides to megabase units, could be the molecular cause of new fragile sites, or other chromosomal lesions. This review focuses on repeat-associated fragility, covering their induction, cytogenetics, epigenetics, cell type specificity, genetic instability (repeat instability, micronuclei, deletions/rearrangements, and sister chromatid exchange), unusual heritability, disease association, and penetrance. Understanding tandem repeat-associated chromosomal fragile sites provides insight to chromosome structure, genome packaging, genetic instability, and disease.

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“…Centromeric (ALR for alpha-like repeats, and GSAT for gamma satellites) and pericentric satellite repeats (BSR for beta satellite repeats, and HSATI, II and HSATIII) together make up around 6.2% of the human genome, according to the recent Telomere-to-Telomere Consortium study [ 19 ]. The classical human satellite DNAs, HSAT, also referred to as human satellites 1, 2 and 3 (HSat1, HSat2, HSat3, or collectively HSat1–3), occur on most human chromosomes as large, pericentromeric tandem repeat arrays, (100 megabases, on average) [ 20 ]. Even though HSat1–3 were among the first human DNA sequences to be isolated and characterized, they have remained almost entirely missing from the human genome reference assembly for 20 years, thus hindering studies of their sequence, regulation, and potential structural roles in the nucleus.…”

Section: Overview Of Repeat Elements: Genomic Organization and Transc...mentioning

confidence: 99%

“…Even though HSat1–3 were among the first human DNA sequences to be isolated and characterized, they have remained almost entirely missing from the human genome reference assembly for 20 years, thus hindering studies of their sequence, regulation, and potential structural roles in the nucleus. Recently, the Telomere-to-Telomere Consortium produced the first truly complete assembly of a human genome [ 21 ], paving the way for new studies of HSat1–3 with modern genomics [ 20 ] and their impact on human health and disease.…”

Section: Overview Of Repeat Elements: Genomic Organization and Transc...mentioning

confidence: 99%

Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer?

et al. 2022

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The human genome is composed of unique DNA sequences that encode proteins and unique sequence noncoding RNAs that are essential for normal development and cellular differentiation. The human genome also contains over 50% of genome sequences that are repeat in nature (tandem and interspersed repeats) that are now known to contribute dynamically to genetic diversity in populations, to be transcriptionally active under certain physiological conditions, and to be aberrantly active in disease states including cancer, where consequences are pleiotropic with impact on cancer cell phenotypes and on the tumor immune microenvironment. Repeat element-derived RNAs play unique roles in exogenous and endogenous cell signaling under normal and disease conditions. A key component of repeat element-derived transcript-dependent signaling occurs via triggering of innate immune receptor signaling that then feeds forward to inflammatory responses through interferon and NFκB signaling. It has recently been shown that cancer cells display abnormal transcriptional activity of repeat elements and that this is linked to either aggressive disease and treatment failure or to improved prognosis/treatment response, depending on cell context and the amplitude of the so-called ‘viral mimicry’ response that is engaged. ‘Viral mimicry’ refers to a cellular state of active antiviral response triggered by endogenous nucleic acids often derived from aberrantly transcribed endogenous retrotransposons and other repeat elements. In this paper, the literature regarding transcriptional activation of repeat elements and engagement of inflammatory signaling in normal (focusing on hematopoiesis) and cancer is reviewed with an emphasis on the role of innate immune receptor signaling, in particular by dsRNA receptors of the RIG-1 like receptor family and interferons/NFκB. How repeat element-derived RNA reprograms cell identity through RNA-guided chromatin state modulation is also discussed.

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A classical revival: Human satellite DNAs enter the genomics era

Cited by 34 publications

References 162 publications

Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines

Overexpression of Pericentromeric HSAT2 DNA Increases Expression of EMT Markers in Human Epithelial Cancer Cell Lines

Fragile sites, chromosomal lesions, tandem repeats, and disease

Repeat Element Activation-Driven Inflammation: Role of NFκB and Implications in Normal Development and Cancer?

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