PMID- 28401797 OWN - NLM STAT- MEDLINE DCOM- 20180321 LR - 20180508 IS - 1557-8534 (Electronic) IS - 1547-3287 (Linking) VI - 26 IP - 13 DP - 2017 Jul 1 TI - The State of Skewed X Chromosome Inactivation is Retained in the Induced Pluripotent Stem Cells from a Female with Hemophilia B. PG - 1003-1011 LID - 10.1089/scd.2016.0323 [doi] AB - Skewed X chromosome inactivation (XCI) is a rare reason for hemophilia B in females. It is indefinite whether X chromosome reactivation (XCR) would occur when cells of hemophilia B patients with skewed XCI were reprogrammed into induced pluripotent stem cells (iPSCs). In this study, we investigated a female hemophilia B patient with a known F9 gene mutation: c.676C>T, p.Arg226Trp. We demonstrated that skewed XCI was the pathogenesis of the patient, and we successfully generated numerous iPSC colonies of the patient from peripheral blood mononuclear cells (PBMNCs), which was the first time for generating hemophilia-specific iPSCs from PBMNCs. Then we detected the XCI state of these iPSCs. Ninety-two iPSC lines were picked for XCI analysis. All of them retained an inactive X chromosome, which could be proved by amplification of the androgen receptor gene and XIST (X inactivation-specific transcript), expression of H3K27me3, and existence of XIST clouds in XIST RNA fluorescence in situ hybridization (FISH) analysis. We attempted to obtain iPSC lines with the wild-type F9 gene on the active X chromosome for further disease treatment. But it turned out that the patient's iPSCs were still skewed such as the somatic cells with 92 iPSC lines having mutant F9 on the active X chromosome. In conclusion, skewed XCI is one reason for hemophilia in females. PBMNCs are excellent somatic cell resources for hemophilia patients to do reprogramming. More attentions should be paid to generate naive iPSCs with two active X chromosomes for further clinical disease treatment. The state of skewed XCI is retained in the iPSCs from a female with hemophilia B. FAU - Lyu, Cuicui AU - Lyu C AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . AD - 2 Department of Hematology, The First Central Hospital of Tianjin , Tianjin, China . FAU - Shen, Jun AU - Shen J AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Zhang, Jianping AU - Zhang J AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Xue, Feng AU - Xue F AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Liu, Xiaofan AU - Liu X AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Liu, Wei AU - Liu W AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Fu, Rongfeng AU - Fu R AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Zhang, Liyan AU - Zhang L AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Li, Huiyuan AU - Li H AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Zhang, Donglei AU - Zhang D AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Zhang, Xiaobing AU - Zhang X AD - 3 Division of Regenerative Medicine MC1528B, Department of Medicine, Loma Linda University , Loma Linda, California. FAU - Cheng, Tao AU - Cheng T AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Yang, Renchi AU - Yang R AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . FAU - Zhang, Lei AU - Zhang L AD - 1 State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China . LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170322 PL - United States TA - Stem Cells Dev JT - Stem cells and development JID - 101197107 RN - 0 (RNA, Long Noncoding) SB - IM MH - Cellular Reprogramming/*genetics MH - Chromosomes, Human, X/genetics MH - Female MH - Gene Expression Regulation, Developmental/genetics MH - Hemophilia B/*genetics/pathology MH - Humans MH - In Situ Hybridization, Fluorescence MH - Induced Pluripotent Stem Cells/*metabolism MH - Leukocytes, Mononuclear/metabolism MH - RNA, Long Noncoding/genetics MH - X Chromosome Inactivation/*genetics OTO - NOTNLM OT - X chromosome inactivation OT - XIST noncoding RNA OT - hemophilia B OT - high-throughput nucleotide sequencing OT - induced pluripotent stem cells EDAT- 2017/04/13 06:00 MHDA- 2018/03/22 06:00 CRDT- 2017/04/13 06:00 PHST- 2017/04/13 06:00 [pubmed] PHST- 2018/03/22 06:00 [medline] PHST- 2017/04/13 06:00 [entrez] AID - 10.1089/scd.2016.0323 [doi] PST - ppublish SO - Stem Cells Dev. 2017 Jul 1;26(13):1003-1011. doi: 10.1089/scd.2016.0323. Epub 2017 Mar 22.