Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs

Cruvinel, Estela; Budinetz, T.H.; Germain, Noélle D.; Chamberlain, Stormy J.; Lalande, Marc; Martins-Taylor, Kristen

doi:10.1093/hmg/ddu187

Cited by 57 publications

(47 citation statements)

References 42 publications

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“…Both H3K9me2 (dimethylation of H3K9) 15,17 and H3K9me3 (trimethylation of H3K9) 37 are associated with the maternal chromosome in the PWS region. We verified differential histone modifications of the PWS-IC by a chromatin immunoprecipitation (ChIP) assay, in which H3K9me2 and H3ac (acetylation of H3) were enriched at the maternal or paternal PWS-IC, respectively (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Kim

Lee

Xiong

et al. 2016

Nat Med

108

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Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. The regulation of imprinted gene expression in this region is coordinated by an imprinting center (PWS-IC). In individuals with PWS, genes responsible for PWS on the maternal chromosome are present, but repressed epigenetically, which provides an opportunity for the use of epigenetic therapy to restore expression from the maternal copies of PWS-associated genes. Through a high-content screen (HCS) of >9,000 small molecules, we discovered that UNC0638 and UNC0642—two selective inhibitors of euchromatic histone lysine N-methyltransferase-2 (EHMT2, also known as G9a)—activated the maternal (m) copy of candidate genes underlying PWS, including the SnoRNA cluster SNORD116, in cells from humans with PWS and also from a mouse model of PWS carrying a paternal (p) deletion from small nuclear ribonucleoprotein N (Snrpn (S)) to ubiquitin protein ligase E3A (Ube3a (U)) (mouse model referred to hereafter as m+/pΔS−U). Both UNC0642 and UNC0638 caused a selective reduction of the dimethylation of histone H3 lysine 9 (H3K9me2) at PWS-IC, without changing DNA methylation, when analyzed by bisulfite genomic sequencing. This indicates that histone modification is essential for the imprinting of candidate genes underlying PWS. UNC0642 displayed therapeutic effects in the PWS mouse model by improving the survival and the growth of m+/pΔS−U newborn pups. This study provides the first proof of principle for an epigenetics-based therapy for PWS.

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Section: Resultsmentioning

confidence: 99%

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Kim

Lee

Xiong

et al. 2016

Nat Med

108

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“…The role of the snoRD113, snoRD114 and snoRD116 cluster region is becoming an important molecular target 78. For example, genetic mapping of snoRD116 has been recently reported to be absent or change its expression and affect other snoRNAs in Prader-Willi syndrome (PWS), a complex rare genetic condition caused by a loss of normally expressed genes on chromosome 15 from the paternal parent 79, 80. It is known that snoRD42A regulates snoRD116 clusters 81, and in our TNBC samples, both snoRNAs (snoRD42A and snoRD116) were found to be drastically under expressed.…”

Section: Resultsmentioning

confidence: 99%

A Comprehensive NGS Data Analysis of Differentially Regulated miRNAs, piRNAs, lncRNAs and sn/snoRNAs in Triple Negative Breast Cancer

Koduru¹,

Tiwari²,

Leberfinger³

et al. 2017

J. Cancer

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Cancer is the second leading cause of death in the United States and is a major public health concern worldwide. Basic, clinical and epidemiological research is leading to improved cancer detection, prevention, and outcomes. Recent technological advances have allowed unbiased and comprehensive screening of genome-wide gene expression. Small non-coding RNAs (sncRNAs) have been shown to play an important role in biological processes and could serve as a diagnostic, prognostic and therapeutic biomarker for specific diseases. Recent findings have begun to reveal and enhance our understanding of the complex architecture of sncRNA expression including miRNAs, piRNAs, lncRNAs, sn/snoRNAs and their relationships with biological systems. We used publicly available small RNA sequencing data that was derived from 24 triple negative breast cancers (TNBC) and 14 adjacent normal tissue samples to remap various types of sncRNAs. We found a total of 55 miRNAs were aberrantly expressed (p<0.005) in TNBC samples (8 miRNAs upregulated; 47 downregulated) compared to adjacent normal tissues whereas the original study reported only 25 novel miRs. In this study, we used pathway analysis of differentially expressed miRNAs which revealed TGF-beta signaling pathways to be profoundly affected in the TNBC samples. Furthermore, our comprehensive re-mapping strategy allowed us to discover a number of other differentially expressed sncRNAs including piRNAs, lncRNAs, sn/snoRNAs, rRNAs, miscRNAs and nonsense-mediated decay RNAs. We believe that our sncRNA analysis workflow is extremely comprehensive and suitable for discovery of novel sncRNAs changes, which may lead to the development of innovative diagnostic and therapeutic tools for TNBC.

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“…13 However, iPSCs with in vitro multipotency have been an invaluable tool to clarify molecular mechanisms as a simulator of developmental defects. 14,15 PRACTICAL ADVICE BEFORE YOU BEGIN These exemplary cases certainly make us feel hopeful that we can apply patient iPSCs to various diseases. Taking all the progress and current issues into consideration, which we discuss more in detail in the following section, we have compiled practical tips you may find useful when starting patient iPSC research.…”

Section: Imprinting Disordersmentioning

confidence: 99%

A practical guide to induced pluripotent stem cell research using patient samples

Santostefano

Hamazaki

Biel

et al. 2015

Laboratory Investigation

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Approximately 3 years ago, we assessed how patient induced pluripotent stem cell (iPSC) research could potentially impact human pathobiology studies in the future. Since then, the field has grown considerably with numerous technical developments, and the idea of modeling diseases 'in a dish' is becoming increasingly popular in biomedical research. Likely, it is even acceptable to include patient iPSCs as one of the standard research tools for disease mechanism studies, just like knockout mice. However, as the field matures, we acknowledge there remain many practical limitations and obstacles for their genuine application to understand diseases, and accept that it has not been as straightforward to model disorders as initially proposed. A major practical challenge has been efficient direction of iPSC differentiation into desired lineages and preparation of the large numbers of specific cell types required for study. Another even larger obstacle is the limited value of in vitro outcomes, which often do not closely represent disease conditions. To overcome the latter issue, many new approaches are underway, including three-dimensional organoid cultures from iPSCs, xenotransplantation of human cells to animal models and in vitro interaction of multiple cell types derived from isogenic iPSCs. Here we summarize the areas where patient iPSC studies have provided truly valuable information beyond existing skepticism, discuss the desired technologies to overcome current limitations and include practical guidance for how to utilize the resources. Undoubtedly, these human patient cells are an asset for experimental pathology studies. The future rests on how wisely we use them.

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Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs

Cited by 57 publications

References 42 publications

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

A Comprehensive NGS Data Analysis of Differentially Regulated miRNAs, piRNAs, lncRNAs and sn/snoRNAs in Triple Negative Breast Cancer

A practical guide to induced pluripotent stem cell research using patient samples

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