DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

Kisseljova, N. P.; Dmitriev, Petr; Kim, Elena; Ezeriņa, Daria; Markozashvili, Diana; Malysheva, D. N.; Planche, Emmeline; Lemmers, Richard J.L.F.; Maarel, Silvère M. van der; Laoudj-Chenivesse, Dalila; Lipinski, Marc; Vassetzky, Yegor S.

doi:10.1038/ejhg.2013.306

Cited by 15 publications

(17 citation statements)

References 41 publications

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“…The association of this S/MAR with the nuclear matrix is regulated by its epigenetic status and diminished in FSHD myogenic cells compared with controls (84,120). The D4Z4 region and neighboring genes usually lie in two chromatin loops, whereas loss of nuclear matrix attachment in FSHD resulted in formation of a single loop due to loss of methylation of a single CpG and the presence of H3K9 acetylation (84,120). In this study, loss of this functional boundary element in FSHD cells allowed a transcriptional enhancer located within D4Z4 to effect de-repression of the proximal genes (119).…”

Section: D4z4 Chromatinmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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Significance: Aberrant epigenetic regulation is an integral aspect of many diseases and complex disorders. Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, is caused by disrupted genetic and epigenetic regulation of a macrosatellite repeat. FSHD provides a powerful model to investigate disease-relevant epigenetic modifiers and general mechanisms of epigenetic regulation that govern gene expression. Recent Advances: In the context of a genetically permissive allele, the one aspect of FSHD that is consistent across all known cases is the aberrant epigenetic state of the disease locus. In addition, certain mutations in the chromatin regulator SMCHD1 (structural maintenance of chromosomes hinge-domain protein 1) are sufficient to cause FSHD2 and enhance disease severity in FSHD1. Thus, there are multiple pathways to generate the epigenetic dysregulation required for FSHD. Critical Issues: Why do some individuals with the genetic requirements for FSHD develop disease pathology, while others remain asymptomatic? Similarly, disease progression is highly variable among individuals. What are the relative contributions of genetic background and environmental factors in determining disease manifestation, progression, and severity in FSHD? What is the interplay between epigenetic factors regulating the disease locus and which, if any, are viable therapeutic targets? Future Directions: Epigenetic regulation represents a potentially powerful therapeutic target for FSHD. Determining the epigenetic signatures that are predictive of disease severity and identifying the spectrum of disease modifiers in FSHD are vital to the development of effective therapies.

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Section: D4z4 Chromatinmentioning

confidence: 99%

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Himeda

Jones

2015

Antioxidants & Redox Signaling

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“…Moreover, the histone enrichment levels were quite different among cell lines, suggesting that neither H4Ac nor H3K9me3, chromatin enrichments, are linked to S/MARs. Indeed, a link between the association of these regions to the NM and active histone marks remains controversial [13,24,40]. These results, suggest that nuclear matrix fixation and chromatin epigenetic status can be independent.…”

Section: Results and Discussion Association Of S/mars In Breast Cellmentioning

confidence: 99%

“…Scaffold Attachment Regions (SARs) can be enriched in H4Ac [23]. The attachment of human S/MARs to the nuclear matrix de-pends on a high DNA methylation level and the absence of H3K9ac within S/MAR [24]. Interestingly, some histone modification enzymes such as HATs are associated with NM [25].…”

mentioning

confidence: 99%

Chromatin enrichment of histone marks H4Ac and H3K9me3 in TP53 gene domain in breast cells

2014

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In non-cancerous breast cell lines HB2 and MCF10A the TP53 gene is localized inside a relatively small~50 kb loop domain delimited by two S/MARs. Aim. To analyze the chromatin markers H4Ac and H3K9me3 of these two S/MARs and of the TP53 gene P1 promoter in different breast cells lines. Methods. We used chromatin immunoprecipitation (ChIP) to characterize the chromatin status of these S/MARs elements in breast non-cancerous cell lines HB2 and MCF10A and cancerous MCF-7, MDA-MB-231, BT-474 and T47D cell lines, by chromatin enrichment of H4Ac and H3K9me3 epigenetic markers, hallmarks of open and closed chromatin, respectively. Results. We found that these chromatin epigenetic markers are differentially distributed in S/MARs for all analyzed breast cell lines. Conclusions. We found no correlation between S/MARs and chromatin epigenetic status, suggesting that nuclear matrix fixation and chromatin status can be independent. High enrichment of H3K9me3 in the TP53 gene P1 promoter region in MCF-7, could explain lower levels of the TP53 expression, described earlier by our group.

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“…Epigenetic marks such as DNA methylation have been shown to be important for attachment of certain MARs to the nuclear matrix [66], and in this way could influence transgene expression, as the nuclear matrix was reported to be enriched in general transcription and RNA processing activities [4–5]. MAR elements have been shown to play a role in maintaining a methylation‐free zone (reviewed in [17]) and including MAR(s) in expression vectors has been shown to prevent de novo methylation of the transgene [67, 68], although they were unable to reverse DNA that was already methylated [67].…”

Section: Epigenetic Elements To Improve Recombinant Protein Productmentioning

confidence: 99%

Epigenetic regulatory elements: Recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells

Harraghy

Calabrese²,

Fisch³

et al. 2015

Biotechnology Journal

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Successful generation of high producing cell lines requires the generation of cell clones expressing the recombinant protein at high levels and the characterization of the clones' ability to maintain stable expression levels. The use of cis-acting epigenetic regulatory elements that improve this otherwise long and uncertain process has revolutionized recombinant protein production. Here we review and discuss new insights into the molecular mode of action of the matrix attachment regions (MARs) and ubiquitously-acting chromatin opening elements (UCOEs), i.e. cis-acting elements, and how these elements are being used to improve recombinant protein production. These elements can help maintain the chromatin environment of the transgene genomic integration locus in a transcriptionally favorable state, which increases the numbers of positive clones and the transgene expression levels. Moreover, the high producing clones tend to be more stable in long-term cultures even in the absence of selection pressure. Therefore, by increasing the probability of isolating a high producing clone, as well as by increasing transcription efficiency and stability, these elements can significantly reduce the time and cost required for producing large quantities of recombinant proteins.

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DNA polymorphism and epigenetic marks modulate the affinity of a scaffold/matrix attachment region to the nuclear matrix

Cited by 15 publications

References 41 publications

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Facioscapulohumeral Muscular Dystrophy As a Model for Epigenetic Regulation and Disease

Chromatin enrichment of histone marks H4Ac and H3K9me3 in TP53 gene domain in breast cells

Epigenetic regulatory elements: Recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells

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