X Chromosome of Female Cells Shows Dynamic Changes in Status during Human Somatic Cell Reprogramming

Kim, Kun-Yong; Hysolli, Eriona; Tanaka, Yoshiaki; Wang, Brandon; Jung, Yong Wook; Pan, Xinghua; Weissman, Sherman M.; Park, In‐Hyun

doi:10.1016/j.stemcr.2014.04.003

Cited by 36 publications

(42 citation statements)

References 43 publications

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“…This suggests that MET is required in both early and intermediate phases and promotes the exit of human reprogramed cells from the type I stage. Consistent with our previous finding that human female fibroblasts reactivate their inactive X chromosome during hiPSC reprogramming (Kim et al., 2014b), X-chromosome inactivation (XCI)-related genes are significantly repressed in fibroblast-to-I (FDR = 0.047) and are induced in III-to-ESC/iPSC stage (FDR = 0.042).…”

Section: Resultssupporting

confidence: 93%

Transcriptome Signature and Regulation in Human Somatic Cell Reprogramming

Tanaka

Hysolli

et al. 2015

Stem Cell Reports

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SummaryReprogramming of somatic cells produces induced pluripotent stem cells (iPSCs) that are invaluable resources for biomedical research. Here, we extended the previous transcriptome studies by performing RNA-seq on cells defined by a combination of multiple cellular surface markers. We found that transcriptome changes during early reprogramming occur independently from the opening of closed chromatin by OCT4, SOX2, KLF4, and MYC (OSKM). Furthermore, our data identify multiple spliced forms of genes uniquely expressed at each progressive stage of reprogramming. In particular, we found a pluripotency-specific spliced form of CCNE1 that is specific to human and significantly enhances reprogramming. In addition, single nucleotide polymorphism (SNP) expression analysis reveals that monoallelic gene expression is induced in the intermediate stages of reprogramming, while biallelic expression is recovered upon completion of reprogramming. Our transcriptome data provide unique opportunities in understanding human iPSC reprogramming.

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Section: Resultssupporting

confidence: 93%

Transcriptome Signature and Regulation in Human Somatic Cell Reprogramming

Tanaka

Hysolli

et al. 2015

Stem Cell Reports

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“…Partially reflecting stem cell quality and derivation conditions, human ESCs and iPSCs can display various different X-chromosome states ranging from mouse-like XCR (Class I) over having achieved XCI (Class II) to an erosion of previously accomplished XCI (Class III). [17][18][19][20][21][22][95][96][97] In order to ensure the safety and quality of human pluripotent stem cells in regenerative medicine, it will be necessary to further investigate the mechanistic basis for their epigenetic variability. Differences between human and mouse XCI also exist on several other levels, including the organization of the XIC, the number of genes escaping XCI and the chromatin status of the inactive X-chromosome.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Payer

Lee

2014

RNA Biology

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X -chromosome inactivation (XCI)in female mammals is a dramatic example of epigenetic gene regulation, which entails the silencing of an entire chromosome through a wide range of mechanisms involving noncoding RNAs, chromatin-modifications, and DNAmethylation. While XCI is associated with the differentiated cell state, it is reversed by X-chromosome reactivation (XCR) ex vivo in pluripotent stem cells and in vivo in the early mouse embryo and the germline. Critical in the regulation of XCI vs. XCR is the X-inactivation center, a multigene locus on the X-chromosome harboring several long noncoding RNA genes including, most prominently, Xist and Tsix. These genes, which sit at the top of the XCI hierarchy, are by themselves controlled by pluripotency factors, coupling XCR with the naïve pluripotent stem cell state. In this point-of-view article we review the latest findings regarding this intricate relationship between cell differentiation state and epigenetic control of the X-chromosome. In particular, we discuss the emerging picture of complex multifactorial regulatory mechanisms, ensuring both a finetuned and robust X-reactivation process.

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“…Given the importance of XCI in vivo , the X-chromosome state of human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) has been addressed by a number of researchers, arriving at the conclusion that these cells have different XCI-states (Anguera et al, 2012; Barakat et al, 2015; Hall et al, 2008; Hoffman et al, 2005; Kim et al, 2014; Lengner et al, 2010; Mekhoubad et al, 2012; Nazor et al, 2012; Pomp et al, 2011; Shen et al, 2008; Silva et al, 2008; Tchieu et al, 2010; Tomoda et al, 2012; Vallot et al, 2015; Xie et al, 2016). At least four X-chromosome states have been described: (i) two active X-chromosomes without XIST expression (XaXa); (ii) an XIST RNA-coated Xi with an Xa (Xi XIST + Xa); (iii) an Xi lacking XIST expression with an Xa (XiXa); and (iv) an Xi lacking XIST RNA with partial loss – erosion – of its silent state (eroded Xi, Xe) with an Xa (XeXa).…”

Section: Introductionmentioning

confidence: 99%

Human Embryonic Stem Cells Do Not Change Their X Inactivation Status during Differentiation

et al. 2017

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SUMMARY Applications of ESCs require faithful chromatin changes during differentiation but the fate of each X-chromosome-state in differentiating ESCs is unclear. Female human ESC-lines either carry two active X-chromosomes (XaXa), an Xa and inactive-X-chromosome with or without XIST-RNA-coating (XiXIST+Xa;XiXa), or an Xa and an eroded-Xi (XeXa) where the Xi no longer expresses XIST-RNA and has partially reactivated. Here, we established XiXa, XeXa, and XaXa ESC-lines and followed their X-chromosome-state during differentiation. Surprisingly, we found that the X-state pre-existing in primed ESCs is maintained in differentiated cells. Consequently, differentiated XeXa and XaXa cells lacked XIST, did not initiate X-inactivation, and displayed higher X-linked gene-expression than XiXa cells. These results demonstrate that X-chromosome-dosage-compensation is not required for ESC differentiation. Our data imply that XiXIST+Xa ESCs are most suited for downstream applications and show that all other X-states are abnormal byproducts of our ESC-derivation and propagation methods.

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X Chromosome of Female Cells Shows Dynamic Changes in Status during Human Somatic Cell Reprogramming

Cited by 36 publications

References 43 publications

Transcriptome Signature and Regulation in Human Somatic Cell Reprogramming

Transcriptome Signature and Regulation in Human Somatic Cell Reprogramming

Coupling of X-Chromosome reactivation with the pluripotent stem cell state

Human Embryonic Stem Cells Do Not Change Their X Inactivation Status during Differentiation

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