The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases

AbstractShort tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS.One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

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Variable numbers of simple tandem repeats make birds of the order Ciconiiformes heteroplasmic in their mitochondrial genomes

Current Genetics ◽

10.1007/bf00326158 ◽

1995 ◽

Vol 27 (3) ◽

pp. 257-262 ◽

Cited By ~ 44

Author(s):

Thomas Berg ◽

Truls Moum ◽

Steinar Johansen

Keyword(s):

Tandem Repeats ◽

Mitochondrial Genomes ◽

Simple Tandem Repeats

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Tandem repeats discovery service (TReaDS) applied to finding novel cis-acting factors in repeat expansion diseases

BMC Bioinformatics ◽

10.1186/1471-2105-13-s4-s3 ◽

2012 ◽

Vol 13 (Suppl 4) ◽

pp. S3 ◽

Cited By ~ 9

Author(s):

Marco Pellegrini ◽

Maria Elena Renda ◽

Alessio Vecchio

Keyword(s):

Tandem Repeats ◽

Repeat Expansion ◽

Cis Acting ◽

Discovery Service

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Genetic drivers of repeat expansion disorders localize to 3-D chromatin domain boundaries

10.1101/191213 ◽

2017 ◽

Cited By ~ 3

Author(s):

James Sun ◽

Linda Zhou ◽

Daniel J. Emerson ◽

Thomas G. Gilgenast ◽

Katelyn Titus ◽

...

Keyword(s):

Dna Sequences ◽

Tandem Repeats ◽

Cpg Island ◽

Fragile X ◽

Repeat Expansion ◽

Chromatin Domain ◽

Epigenetic Instability ◽

Mechanistic Basis ◽

Severe Pathology ◽

Short Tandem

AbstractMore than 25 inherited neurological disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why specific STRs are susceptible to unstable expansion leading to severe pathology, whereas tens of thousands of normal-length repeat tracts across the human genome are relatively stable. Here, we unexpectedly discover that nearly all STRs associated with repeat expansion diseases are located at boundaries demarcating 3-D chromatin domains. We find that boundaries exhibit markedly higher CpG island density compared to loci internal to domains. Importantly, disease-associated STRs are specifically localized to ultra-dense CpG island-rich boundaries, suggesting that these loci might be hotspots for epigenetic instability and topological disruption upon unstable expansion. In Fragile X Syndrome, mutation-length expansion at the Fmr1 gene results in severe disruption of the boundary between TADs. Our data uncover higher-order chromatin architecture as a new dimension in understanding the mechanistic basis of repeat expansion disorders.

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The molecular pathogenesis of repeat expansion diseases

Biochemical Society Transactions ◽

10.1042/bst20200143 ◽

2021 ◽

Author(s):

Yuzo Fujino ◽

Yoshitaka Nagai

Keyword(s):

Tandem Repeats ◽

Research Direction ◽

Repeat Expansion ◽

Repeat Sequence ◽

Loss Of Function ◽

Cgg Repeat ◽

Function Mechanism ◽

Coding Regions ◽

Monogenic Diseases ◽

Common Pathogenesis

Expanded short tandem repeats in the genome cause various monogenic diseases, particularly neurological disorders. Since the discovery of a CGG repeat expansion in the FMR1 gene in 1991, more than 40 repeat expansion diseases have been identified to date. In the coding repeat expansion diseases, in which the expanded repeat sequence is located in the coding regions of genes, the toxicity of repeat polypeptides, particularly misfolding and aggregation of proteins containing an expanded polyglutamine tract, have been the focus of investigation. On the other hand, in the non-coding repeat expansion diseases, in which the expanded repeat sequence is located in introns or untranslated regions, the toxicity of repeat RNAs has been the focus of investigation. Recently, these repeat RNAs were demonstrated to be translated into repeat polypeptides by the novel mechanism of repeat-associated non-AUG translation, which has extended the research direction of the pathological mechanisms of this disease entity to include polypeptide toxicity. Thus, a common pathogenesis has been suggested for both coding and non-coding repeat expansion diseases. In this review, we briefly outline the major pathogenic mechanisms of repeat expansion diseases, including a loss-of-function mechanism caused by repeat expansion, repeat RNA toxicity caused by RNA foci formation and protein sequestration, and toxicity by repeat polypeptides. We also discuss perturbation of the physiological liquid-liquid phase separation state caused by these repeat RNAs and repeat polypeptides, as well as potential therapeutic approaches against repeat expansion diseases.

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Intragenic repeat expansions control yeast chronological aging

10.1101/653006 ◽

2019 ◽

Cited By ~ 2

Author(s):

Benjamin P Barré ◽

Johan Hallin ◽

Jia-Xing Yue ◽

Karl Persson ◽

Ekaterina Mikhalev ◽

...

Keyword(s):

Life Span ◽

Calorie Restriction ◽

Molecular Mechanisms ◽

Tandem Repeats ◽

Repeat Expansion ◽

Yeast Cells ◽

Chronological Aging ◽

Cellular Life ◽

Chronological Life Span ◽

Repeat Expansions

ABSTRACTAging varies among individuals due to both genetics and environment but the underlying molecular mechanisms remain largely unknown. Using a highly recombinedSaccharomyces cerevisiaepopulation, we found 30 distinct Quantitative Trait Loci (QTLs) that control chronological life span (CLS) in calorie rich and calorie restricted environments, and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes, but through different genetic variants. We tracked the two major QTLs to massive expansions of intragenic tandem repeats in the cell wall glycoproteinsFLO11andHPF1, which caused a dramatic life span shortening. Life span impairment by N-terminalHPF1repeat expansion was partially buffered by rapamycin but not by calorie restriction. TheHPF1repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation perturbed methionine, lipid, and purine metabolism, which likely explains the life span shortening. We conclude that fast evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular life style and longevity.

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On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Journal of Biological Chemistry ◽

10.1074/jbc.rev119.007678 ◽

2020 ◽

Vol 295 (13) ◽

pp. 4134-4170 ◽

Cited By ~ 27

Author(s):

Alexandra N. Khristich ◽

Sergei M. Mirkin

Keyword(s):

Molecular Mechanisms ◽

Tandem Repeats ◽

Genome Instability ◽

Current Knowledge ◽

Model Systems ◽

Dna Repeats ◽

Repeat Instability ◽

Repeat Expansions ◽

Induced Mutagenesis ◽

Simple Tandem Repeats

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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A naturally occurring, noncanonical GTP aptamer made of simple tandem repeats

RNA Biology ◽

10.4161/rna.28798 ◽

2014 ◽

Vol 11 (6) ◽

pp. 682-692 ◽

Cited By ~ 5

Author(s):

Edward A Curtis ◽

David R Liu

Keyword(s):

Tandem Repeats ◽

Naturally Occurring ◽

Simple Tandem Repeats

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Identification of DNA cis Elements Essential for Expansion of Ribosomal DNA Repeats inSaccharomyces cerevisiae

Molecular and Cellular Biology ◽

10.1128/mcb.21.1.136-147.2001 ◽

2001 ◽

Vol 21 (1) ◽

pp. 136-147 ◽

Cited By ~ 41

Author(s):

Takehiko Kobayashi ◽

Masayasu Nomura ◽

Takashi Horiuchi

Keyword(s):

Ribosomal Dna ◽

Tandem Repeats ◽

Mutational Analysis ◽

Hot Spot ◽

Repeat Expansion ◽

5S Rrna ◽

Rrna Gene ◽

Dna Repeats ◽

Rdna Repeat ◽

5S Rrna Gene

ABSTRACT Saccharomyces cerevisiae carries ∼150 ribosomal DNA (rDNA) copies in tandem repeats. Each repeat consists of the 35S rRNA gene, the NTS1 spacer, the 5S rRNA gene, and the NTS2 spacer. TheFOB1 gene was previously shown to be required for replication fork block (RFB) activity at the RFB site in NTS1, for recombination hot spot (HOT1) activity, and for rDNA repeat expansion and contraction. We have constructed a strain in which the majority of rDNA repeats are deleted, leaving two copies of rDNA covering the 5S-NTS2-35S region and a single intact NTS1, and whose growth is supported by a helper plasmid carrying, in addition to the 5S rRNA gene, the 35S rRNA coding region fused to the GAL7promoter. This strain carries a fob1 mutation, and an extensive expansion of chromosomal rDNA repeats was demonstrated by introducing the missing FOB1 gene by transformation. Mutational analysis using this system showed that not only the RFB site but also the adjacent ∼400-bp region in NTS1 (together called the EXP region) are required for the FOB1-dependent repeat expansion. This ∼400-bp DNA element is not required for the RFB activity or the HOT1 activity and therefore defines a function unique to rDNA repeat expansion (and presumably contraction) separate from HOT1 and RFB activities.

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Local Tandem Repeat Expansion in Xist RNA as a Model for the Functionalisation of ncRNA

Non-Coding RNA ◽

10.3390/ncrna4040028 ◽

2018 ◽

Vol 4 (4) ◽

pp. 28 ◽

Cited By ~ 11

Author(s):

Neil Brockdorff

Keyword(s):

Tandem Repeat ◽

Tandem Repeats ◽

Rna Binding ◽

Rna Binding Proteins ◽

Repeat Expansion ◽

Chromosome Inactivation ◽

Rna Sequences ◽

Xist Rna ◽

Non Coding Rnas ◽

In Cis

Xist, the master regulator of the X chromosome inactivation in mammals, is a 17 kb lncRNA that acts in cis to silence the majority of genes along the chromosome from which it is transcribed. The two key processes required for Xist RNA function, localisation in cis and recruitment of silencing factors, are genetically separable, at least in part. Recent studies have identified Xist RNA sequences and associated RNA-binding proteins (RBPs) that are important for these processes. Notably, several of the key Xist RNA elements correspond to local tandem repeats. In this review, I use examples to illustrate different modes whereby tandem repeat amplification has been exploited to allow orthodox RBPs to confer new functions for Xist-mediated chromosome inactivation. I further discuss the potential generality of tandem repeat expansion in the evolution of functional long non-coding RNAs (lncRNAs).

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