Nucleosomal occupancy and CGG repeat expansion: a comparative analysis of triplet repeat region from mouse and human fragile X mental retardation gene 1

Datta, Sonal; Alam, Mohammad P.; Majumdar, Subeer S.; Mehta, Abhishek Kumar; Maiti, Souvik; Wadhwa, Neerja; Brahmachari, Vani

doi:10.1007/s10577-011-9206-7

Cited by 10 publications

(6 citation statements)

References 51 publications

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“…Knock-in mouse models in which the murine CGG repeat has been replaced with a premutation-sized CGG repeat from humans were reported to exhibit moderate repeat instability with both paternal and material transmission [35], [36]. However, in addition to CGG-repeat length, since the nature of the flanking sequences in combination with the patterns of interruption of CGG repeats can influence nucleosomal structure and alter CGG repeat instability [37], [38], the use of genetically accurate, human neuronal models will be advantageous to investigate the molecular mechanisms of trinucleotide repeat instability and epigenetic regulation.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

et al. 2011

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Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5′ untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.

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Section: Discussionmentioning

confidence: 99%

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

et al. 2011

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“…To start with, we selected a subset of genomic signatures based on their presumed or demonstrated roles in chromatin structure, DNA replication or repair. Some of these marks have also been associated with repeat instability (Libby et al, 2008 ; Dion and Wilson, 2009 ; Nakamori and Thornton, 2010 ; Datta et al, 2011 ; Cohen-Carmon and Meshorer, 2012 ; Debacker et al, 2012 ; Volle and Delaney, 2012 ). The Roadmap Epigenomics Project (Roadmap Epigenomics Consortium et al, 2015 ) and the ENCODE Project (ENCODE Project Consortium, 2012 ) encompass genome-wide high-quality data sets, which can be utilized to answer specific questions statistically.…”

Section: Methodsmentioning

confidence: 99%

Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions

et al. 2016

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More than 30 human genetic diseases are linked to tri-nucleotide repeat expansions. There is no known mechanism that explains repeat expansions in full, but changes in the epigenetic state of the associated locus has been implicated in the disease pathology for a growing number of examples. A comprehensive comparative analysis of the genomic features associated with diverse repeat expansions has been lacking. Here, in an effort to decipher the propensity of repeats to undergo expansion and result in a disease state, we determine the genomic coordinates of tri-nucleotide repeat tracts at base pair resolution and computationally establish epigenetic profiles around them. Using three complementary statistical tests, we reveal that several epigenetic states are enriched around repeats that are associated with disease, even in cells that do not harbor expansion, relative to a carefully stratified background. Analysis of over one hundred cell types reveals that epigenetic states generally tend to vary widely between genic regions and cell types. However, there is qualified consistency in the epigenetic signatures of repeats associated with disease suggesting that changes to the chromatin and the DNA around an expanding repeat locus are likely to be similar. These epigenetic signatures may be exploited further to develop models that could explain the propensity of repeats to undergo expansions.

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“…However, CGG/CCG repeats in a larger fragment of the human FMR1 gene have previously been shown to form multiple translational positions, and the sequence flanking the repeats has also been shown to alter nucleosome positioning in vivo [37,63]. It is important to consider that the AGG/CCT interruptions are likely altering the rotational and translational positions of the FMR1 substrates in a similar manner as in the S1 substrates, but because of the formation of multiple species of nucleosomes, those changes cannot be detected by this technique.…”

Section: Resultsmentioning

confidence: 99%

AGG/CCT interruptions affect nucleosome formation and positioning of healthy-length CGG/CCG triplet repeats

Volle

Delaney

2013

BMC Biochemistry

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BackgroundFragile X Syndrome (FXS), the most common inherited form of mental retardation, is caused by expansion of a CGG/CCG repeat tract in the 5′-untranslated region of the fragile X mental retardation (FMR1) gene, which changes the functional organization of the gene from euchromatin to heterochromatin. Interestingly, healthy-length repeat tracts possess AGG/CCT interruptions every 9–10 repeats, and clinical data shows that loss of these interruptions is linked to expansion of the repeat tract to disease-length. Thus, it is important to understand how these interruptions alter the behavior of the repeat tract in the packaged gene.ResultsTo investigate how uninterrupted and interrupted CGG/CCG repeat tracts interact with the histone core, we designed experiments using the nucleosome core particle, the most basic unit of chromatin packaging. Using DNA containing 19 CGG/CCG repeats, flanked by either a nucleosome positioning sequence or the FMR1 gene sequence, we determined that the addition of a single AGG/CCT interruption modulates both the ability of the CGG/CCG repeat DNA to incorporate into a nucleosome and the rotational and translational position of the repeat DNA around the histone core when flanked by the nucleosome positioning sequence. The presence of these interruptions also alters the periodicity of the DNA in the nucleosome; interrupted repeat tracts have a greater periodicity than uninterrupted repeats.ConclusionsThis work defines the ability of AGG/CCT interruptions to modulate the behavior of the repeat tract in the packaged gene and contributes to our understanding of the role that AGG/CCT interruptions play in suppressing expansion and maintaining the correct functional organization of the FMR1 gene, highlighting a protective role played by the interruptions in genomic packaging.

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Nucleosomal occupancy and CGG repeat expansion: a comparative analysis of triplet repeat region from mouse and human fragile X mental retardation gene 1

Cited by 10 publications

References 51 publications

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions

AGG/CCT interruptions affect nucleosome formation and positioning of healthy-length CGG/CCG triplet repeats

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