Loss of hierarchical imprinting regulation at the Prader–Willi/Angelman syndrome locus in human iPSCs

Autor: Ana Cláudia Raposo, Mariana Joaquim, Luís Pereira de Almeida, Ana Rita Álvaro, Inês Godinho, Isabel Onofre, Duarte Pólvora-Brandão, Sofia T. Duarte, Simão Teixeira da Rocha, Domenico Aprile
Rok vydání: 2018
Předmět:
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
Ubiquitin-Protein Ligases
Prader-Willi/Angelman syndrome
Induced Pluripotent Stem Cells
HDE NEU PED
Biology
Germline
Genomic Imprinting
03 medical and health sciences
Angelman syndrome
Genetics
medicine
Humans
Regulatory Elements
Transcriptional
Imprinting (psychology)
Allele
Promoter Regions
Genetic
Induced pluripotent stem cell
Molecular Biology
Alleles
Genetics (clinical)
Skin
Chromosomes
Human
Pair 15
Tumor Suppressor Proteins
nutritional and metabolic diseases
General Medicine
DNA Methylation
Fibroblasts
Cellular Reprogramming
medicine.disease
nervous system diseases
Germ Cells
030104 developmental biology
Differentially methylated regions
Ribonucleoproteins
General Article
Angelman Syndrome
Genomic imprinting
Prader-Willi Syndrome
Reprogramming
Zdroj: Human Molecular Genetics
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação
instacron:RCAAP
ISSN: 1460-2083
0964-6906
Popis: The human chr15q11-q13 imprinted cluster is linked to several disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes. Recently, disease modeling approaches based on induced pluripotent stem cells (iPSCs) have been used to study these syndromes. A concern regarding the use of these cells for imprinted disease modeling is the numerous imprinting defects found in many iPSCs. Here, by reprogramming skin fibroblasts from a control and AS individuals, we generated several iPSC lines and addressed the stability of imprinting status across the PWS/AS domain. We focused on three important regulatory DNA elements which are all differentially methylated regions (DMRs), methylated on the maternal allele: the PWS imprinting center (PWS-IC), which is a germline DMR and the somatic NDN and MKRN3 DMRs, hierarchically controlled by PWS-IC. Normal PWS-IC methylation pattern was maintained in most iPSC lines; however, loss of maternal methylation in one out of five control iPSC lines resulted in a monoallelic to biallelic switch for many imprinted genes in this domain. Surprisingly, MKRN3 DMR was found aberrantly hypermethylated in all control and AS iPSCs, regardless of the methylation status of the PWS-IC master regulator. This suggests a loss of hierarchical control of imprinting at PWS/AS region. We confirmed these results in established iPSC lines derived using different reprogramming procedures. Overall, we show that hierarchy of imprinting control in donor cells might not apply to iPSCs, accounting for their spectrum of imprinting alterations. Such differences in imprinting regulation should be taken into consideration for the use of iPSCs in disease modeling. info:eu-repo/semantics/publishedVersion
Databáze: OpenAIRE
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