Loss of hierarchical imprinting regulation at the Prader-Willi/Angelman syndrome locus in human iPSCs.
Loss of hierarchical imprinting regulation at the Prader-Willi/Angelman syndrome locus in human iPSCs.
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DOI：
10.1093/hmg/ddy274
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发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
da Rocha ST
中科院分区：
文献类型：
--
作者：
Pólvora-Brandão D;Joaquim M;Godinho I;Aprile D;Álvaro AR;Onofre I;Raposo AC;Pereira de Almeida L;Duarte ST;da Rocha ST
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.
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由印记基因MKRN3突变引起的中央早熟青春期。
DOI：
10.1056/nejmoa1302160
发表时间：
2013-06-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Abreu AP;Dauber A;Macedo DB;Noel SD;Brito VN;Gill JC;Cukier P;Thompson IR;Navarro VM;Gagliardi PC;Rodrigues T;Kochi C;Longui CA;Beckers D;de Zegher F;Montenegro LR;Mendonca BB;Carroll RS;Hirschhorn JN;Latronico AC;Kaiser UB
通讯作者：
Kaiser UB
DOI：
10.1002/wrna.1150
发表时间：
2013-03
期刊：
Wiley interdisciplinary reviews. RNA
影响因子：
--
作者：
Chamberlain SJ
通讯作者：
Chamberlain SJ
影响因子：
5.2
作者：
Pick, Marjorie;Stelzer, Yonatan;Benvenisty, Nissim
通讯作者：
Benvenisty, Nissim
影响因子：
30.8
作者：
Jay, P;Rougeulle, C;Muscatelli, F
通讯作者：
Muscatelli, F
影响因子：
7.2
作者：
Barlow, Denise P.;Bartolomei, Marisa S.
通讯作者：
Bartolomei, Marisa S.