Specific ZNF274 binding interference at<i>SNORD116</i>activates the maternal transcripts in Prader-Willi syndrome neurons

Langouët, Maéva; Gorka, Dea; Orniacki, Clarisse; Dupont-Thibert, Clémence M; Chung, Michael; Glatt-Deeley, Heather; Germain, Noélle D.; Crandall, Leann; Cotney, Justin; Stoddard, Christopher; Lalande, Marc; Chamberlain, Stormy J.

doi:10.1093/hmg/ddaa210

Cited by 14 publications

(18 citation statements)

References 56 publications

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“…The SNORD116 cluster hosts several binding sites for the ZNF274 protein that are important for local epigenetic regulation during development ( Cruvinel et al 2014 ). Very interestingly, a knockout of the ZNF274 gene or of the ZNF274 protein binding sites at the SNORD116 locus partially rescued expression of the silent maternal SNORD116 alleles in neurons derived from PWS iPSCs (Langouët et al 2018 , 2020 ). Furthermore, the SNORD116 cluster generates a set of long noncoding RNAs (lncRNAs) including sno-lncRNAs that are thought to sequester nuclear proteins in human pluripotent cells ( Yin et al 2012 ; Wu et al 2016 ), but whether these RNA species are involved in PWS has not yet been tested.…”

Section: Introductionmentioning

confidence: 99%

Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader–Willi Syndrome

Baldini

Robert

Charpentier

et al. 2021

Molecular Biology and Evolution

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The eutherian-specific SNORD116 family of repeated box C/D snoRNA genes is suspected to play a major role in the Prader Willi syndrome (PWS), yet its molecular function remains poorly understood. Here, we combined phylogenetic and molecular analyses to identify candidate RNA targets. Based on the analysis of several eutherian orthologs, we found evidence of extensive birth-and-death and conversion events during SNORD116 gene history. However, the consequences for phylogenetic conservation were heterogeneous along the gene sequence. The standard snoRNA elements necessary for RNA stability and association with dedicated core proteins were the most conserved, in agreement with the hypothesis that SNORD116 generate genuine snoRNAs. Also, one of the two antisense elements (ASEs) typically involved in RNA target recognition was largely dominated by a unique sequence present in at least one subset of gene paralogs in most species, likely the result of a selective effect. In agreement with a functional role, this ASE exhibited a hybridization capacity with putative mRNA targets that was strongly conserved in Eutherians. Moreover, transient downregulation experiments in human cells showed that Snord116 controls the expression and splicing levels of these mRNAs. The functions of two of them, diacylglycerol kinase kappa (Dgkk) and Neuroligin 3 (Nlgn3), extend the description of the molecular bases of PWS and reveal unexpected molecular links with the Fragile X syndrome and autism spectrum disorders.

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Section: Introductionmentioning

confidence: 99%

Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader–Willi Syndrome

Baldini

Robert

Charpentier

et al. 2021

Molecular Biology and Evolution

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“…The study results support the notion that ZNF274 recruits SETDB1 to maternal SNORD116, where it deposits another protein H3K9me3 and contributes to repression of the maternal allele. ZNF-274 knock study provided additional support for this hypothesis [73,74].…”

Section: Epigenetic Causementioning

confidence: 74%

Proteins and proteases of Prader–Willi syndrome: a comprehensive review and perspectives

Basak

2022

Bioscience Reports

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Prader–Willi Syndrome (PWS) is a rare complex genetic disease that is associated with pathological disorders that include endocrine disruption, developmental, neurological, and physical problems as well as intellectual, and behavioral dysfunction. In early stage, PWS is characterized by respiratory distress, hypotonia, and poor sucking ability, causing feeding concern and poor weight gain. Additional features of the disease evolve over time. These include hyperphagia, obesity, developmental, cognitive delay, skin picking, high pain threshold, short stature, growth hormone deficiency, hypogonadism, strabismus, scoliosis, joint laxity, or hip dysplasia. The disease is associated with a shortened life expectancy. There is no cure for PWS, although interventions are available for symptoms management. PWS is caused by genetic defects in chromosome 15q11.2-q13, and categorized into three groups, namely Paternal deletion, Maternal uniparental disomy, and Imprinting defect. PWS is confirmed through genetic testing and DNA-methylation analysis. Studies revealed that at least two key proteins namely MAGEL-2 and NECDIN along with two proteases PCSK1 and PCSK2 are linked to PWS. Herein, we summarize our current understanding and knowledge about the role of these proteins and enzymes in various biological processes associated with PWS. The review also describes how loss and/or impairment of functional activity of these macromolecules can lead to hormonal disbalance by promoting degradation of secretory granules and via inhibition of proteolytic maturation of precursor-proteins. The present review will draw attention of researchers, scientists, and academicians engaged in PWS study and will help to identify potential targets and molecular pathways for PWS intervention and treatment.

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“…Thus, further studies are needed to clarify the association between DNA methylation of PWS-ICR and allele-specific distribution of G9a. Meanwhile, the reactivation of SNRPN and SNORD116 was recently achieved by preventing the recruitment of H3K9me3 repressive histone modification-related protein factor to SNORD116 locus in PWS-derived iPSCs ( Langouët et al, 2020 ). In summary, small molecules related epigenetic therapy for PWS through modulating the condition of specific chromatin regions could be a potential strategy to be translated in clinical relevance ( Crunkhorn, 2017 ; Chung et al, 2020 ).…”

Section: Modulation Of the Long Non-coding Rna Ube3a-ats To Rescue Abnormal Imprinting In Prader–willi Syndrome/angelmmentioning

confidence: 99%

The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets

Wang

Jianjian

Yang

et al. 2021

Front. Cell Dev. Biol.

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Genomic imprinting is a term used for an intergenerational epigenetic inheritance and involves a subset of genes expressed in a parent-of-origin-dependent way. Imprinted genes are expressed preferentially from either the paternally or maternally inherited allele. Long non-coding RNAs play essential roles in regulating this allele-specific expression. In several well-studied imprinting clusters, long non-coding RNAs have been found to be essential in regulating temporal- and spatial-specific establishment and maintenance of imprinting patterns. Furthermore, recent insights into the epigenetic pathological mechanisms underlying human genomic imprinting disorders suggest that allele-specific expressed imprinted long non-coding RNAs serve as an upstream regulator of the expression of other protein-coding or non-coding imprinted genes in the same cluster. Aberrantly expressed long non-coding RNAs result in bi-allelic expression or silencing of neighboring imprinted genes. Here, we review the emerging roles of long non-coding RNAs in regulating the expression of imprinted genes, especially in human imprinting disorders, and discuss three strategies targeting the central long non-coding RNA UBE3A-ATS for the purpose of developing therapies for the imprinting disorders Prader–Willi syndrome and Angelman syndrome. In summary, a better understanding of long non-coding RNA-related mechanisms is key to the development of potential therapeutic targets for human imprinting disorders.

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Specific ZNF274 binding interference atSNORD116activates the maternal transcripts in Prader-Willi syndrome neurons

Cited by 14 publications

References 56 publications

Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader–Willi Syndrome

Phylogenetic and Molecular Analyses Identify SNORD116 Targets Involved in the Prader–Willi Syndrome

Proteins and proteases of Prader–Willi syndrome: a comprehensive review and perspectives

The Role of Long Non-coding RNAs in Human Imprinting Disorders: Prospective Therapeutic Targets

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