Mechanisms of transcriptional dysregulation in repeat expansion disorders

Groh, Matthias F.; Silva, Lara Marques; Gromak, Natalia

doi:10.1042/bst20140049

Cited by 32 publications

(25 citation statements)

References 53 publications

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“…These elements have a relatively narrow length distribution, most are longer that 50 nt, indicating that they are under selection, possibly by the requirement to bind CTCF or BORIS. While expansion of short TRs is known to cause disease in a number of studied cases [98, 99], their genome-wide biological role is obscure. Thus, it is likely that BORIS and CTCF co-binding there uncovered a putative regulatory role for these elements in germline and/or cancer transcription.…”

Section: Discussionmentioning

confidence: 99%

The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements

Pugacheva

Teplyakov

et al. 2016

Epigenetics & Chromatin

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BackgroundA common aberration in cancer is the activation of germline-specific proteins. The DNA-binding proteins among them could generate novel chromatin states, not found in normal cells. The germline-specific transcription factor BORIS/CTCFL, a paralog of chromatin architecture protein CTCF, is often erroneously activated in cancers and rewires the epigenome for the germline-like transcription program. Another common feature of malignancies is the changed expression and epigenetic states of genomic repeats, which could alter the transcription of neighboring genes and cause somatic mutations upon transposition. The role of BORIS in transposable elements and other repeats has never been assessed.ResultsThe investigation of BORIS and CTCF binding to DNA repeats in the K562 cancer cells dependent on BORIS for self-renewal by ChIP-chip and ChIP-seq revealed three classes of occupancy by these proteins: elements cohabited by BORIS and CTCF, CTCF-only bound, or BORIS-only bound. The CTCF-only enrichment is characteristic for evolutionary old and inactive repeat classes, while BORIS and CTCF co-binding predominately occurs at uncharacterized tandem repeats. These repeats form staggered cluster binding sites, which are a prerequisite for CTCF and BORIS co-binding. At the same time, BORIS preferentially occupies a specific subset of the evolutionary young, transcribed, and mobile genomic repeat family, SVA. Unlike CTCF, BORIS prominently binds to the VNTR region of the SVA repeats in vivo. This suggests a role of BORIS in SVA expression regulation. RNA-seq analysis indicates that BORIS largely serves as a repressor of SVA expression, alongside DNA and histone methylation, with the exception of promoter capture by SVA.ConclusionsThus, BORIS directly binds to, and regulates SVA repeats, which are essentially movable CpG islands, via clusters of BORIS binding sites. This finding uncovers a new function of the global germline-specific transcriptional regulator BORIS in regulating and repressing the newest class of transposable elements that are actively transposed in human genome when activated. This function of BORIS in cancer cells is likely a reflection of its roles in the germline.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-016-0084-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements

Pugacheva

Teplyakov

et al. 2016

Epigenetics & Chromatin

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“…Repeat expansion sequences are known to inhibit or impede RNA Polymerase II (Pol II) initiation or elongation either directly or via induction of a repressed chromatin state [100]. Expansions like the GAA repeat in FRDA [19, 94, 97, 162, 231], the CTG repeat in myotonic dystrophy type 1 (DM1) [25], the GGGGCC repeat in C9ORF72 -associated frontotemporal dementia and amyotrophic lateral sclerosis (C9FTD/ALS) [108], and the CGG repeat in FXS (also known as FRAXA) [44, 285] have all been implicated in reduced or silenced transcription.…”

Section: Transcription and Splicing At Simple Tandem Repeat Expansionsmentioning

confidence: 99%

RNA biology of disease-associated microsatellite repeat expansions

Rohilla

Gagnon

2017

acta neuropathol commun

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Microsatellites, or simple tandem repeat sequences, occur naturally in the human genome and have important roles in genome evolution and function. However, the expansion of microsatellites is associated with over two dozen neurological diseases. A common denominator among the majority of these disorders is the expression of expanded tandem repeat-containing RNA, referred to as xtrRNA in this review, which can mediate molecular disease pathology in multiple ways. This review focuses on the potential impact that simple tandem repeat expansions can have on the biology and metabolism of RNA that contain them and underscores important gaps in understanding. Merging the molecular biology of repeat expansion disorders with the current understanding of RNA biology, including splicing, transcription, transport, turnover and translation, will help clarify mechanisms of disease and improve therapeutic development.

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“…In addition, the CpG islands destabilize nucleosomes and attract proteins that create a transcriptionally permissive chromatin state [120]. The authors hypothesized that the flanking DNA may modify the downstream processing of aberrant structures by DNA repair machinery through either R-loops or CpG ME effect and/or chromatin dynamics such as CTCF [112,121,122]. Indeed, higher ME levels in CpG island in SCA3 patients have earlier age at onset with the same size of CAG repeats [123].…”

Section: Epigenetic Factorsmentioning

confidence: 99%

DNA repair in trinucleotide repeat ataxias

et al. 2018

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The inherited cerebellar ataxias comprise of a genetic heterogeneous group of disorders. Pathogenic expansions of cytosine-adenine-guanine (CAG) encoding polyglutamine tracts account for the largest proportion of autosomal dominant cerebellar ataxias, while GAA expansion in the first introns of frataxin gene is the commonest cause of autosomal recessive cerebellar ataxias. Currently, there is no available treatment to alter the disease trajectory, with devastating consequences for affected individuals. Inter- and Intrafamily phenotypic variability suggest the existence of genetic modifiers, which may become targets amendable to treatment. Recent studies have demonstrated the importance of DNA repair pathways in modifying spinocerebellar ataxia with CAG repeat expansions. In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

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Mechanisms of transcriptional dysregulation in repeat expansion disorders

Cited by 32 publications

References 53 publications

The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements

The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements

RNA biology of disease-associated microsatellite repeat expansions

DNA repair in trinucleotide repeat ataxias

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