Inherent genomic properties underlie the epigenomic heterogeneity of human induced pluripotent stem cells

Yokobayashi, Shihori; Yabuta, Yukihiro; Nakagawa, Masato; Okita, Keisuke; Hu, Bo; Murase, Yusuke; Nakamura, Tomonori; Bourque, Guillaume; Majewski, Jacek; Yamamoto, Takuya; Saitou, Mitinori

doi:10.1016/j.celrep.2021.109909

Cited by 19 publications

(21 citation statements)

References 87 publications

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“…Two recent studies used human in vitro PGCLC differentiation systems to investigate if the X‐inactivation state of human pluripotent stem cells would affect their propensity to differentiate towards the germ cell lineage. While the first study did not find a significant effect (Chang et al , 2021 ), the second study reported that human iPSCs with eroded X‐inactivation showed a lower efficiency in forming PGCLCs when compared to cells with a higher degree of X‐inactivation (Yokobayashi et al , 2021 ). This suggests that faithful X‐dosage control might be an important feature of both mouse and human germ cell development.…”

Section: Discussionmentioning

confidence: 99%

Controlled X‐chromosome dynamics defines meiotic potential of female mouse in vitro germ cells

et al. 2022

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The mammalian germline is characterized by extensive epigenetic reprogramming during its development into functional eggs and sperm. Specifically, the epigenome requires resetting before parental marks can be established and transmitted to the next generation. In the female germline, X-chromosome inactivation and reactivation are among the most prominent epigenetic reprogramming events, yet very little is known about their kinetics and biological function. Here, we investigate X-inactivation and reactivation dynamics using a tailor-made in vitro system of primordial germ cell-like cell (PGCLC) differentiation from mouse embryonic stem cells. We find that X-inactivation in PGCLCs in vitro and in germ cell-competent epiblast cells in vivo is moderate compared to somatic cells, and frequently characterized by escaping genes. X-inactivation is followed by step-wise X-reactivation, which is mostly completed during meiotic prophase I. Furthermore, we find that PGCLCs which fail to undergo X-inactivation or reactivate too rapidly display impaired meiotic potential. Thus, our data reveal fine-tuned X-chromosome remodelling as a critical feature of female germ cell development towards meiosis and oogenesis.

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Section: Discussionmentioning

confidence: 99%

Controlled X‐chromosome dynamics defines meiotic potential of female mouse in vitro germ cells

et al. 2022

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“…showing KRAB-ZNF gene enrichment and H3K9me3-mediated regulation in cell line-specific signatures suggest possible mechanisms controlling these stable expression phenotypes. Also regulated by H3K9me3 mechanisms, evolutionarily recent transposable elements and their corresponding KRAB-ZNF repressor genes have been directly implicated in human zygotic genome activation and preimplantation states specifying gene expression at later stages of development (65,(80)(81)(82)(83) The genetics of neurodevelopmental disorders (20,21,(84)(85)(86) and human brain evolution (18,(87)(88)(89) are being integrated into cerebral organoid models that parallel in utero and early postnatal brain development (90,91). As PSC-derived models of early human and mouse development become increasingly sophisticated (92)(93)(94)(95), approaches to exploring inherent variation across synthetic embryos from diverse PSC lines will become critical.…”

Section: Discussionmentioning

confidence: 99%

“…Our results showing KRAB-ZNF gene enrichment and H3K9me3-mediated regulation in cell line-specific signatures suggest possible mechanisms controlling these stable expression phenotypes. Also regulated by H3K9me3 mechanisms, evolutionarily recent transposable elements and their corresponding KRAB-ZNF repressor genes have been directly implicated in human zygotic genome activation and preimplantation states specifying gene expression at later stages of development (65, 80–83)…”

Section: Discussionmentioning

confidence: 99%

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Kim¹,

Seo

Stein-O’Brien³

et al. 2021

Preprint

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SUMMARYVariability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. We identify differences in the spontaneous self-organization of individual hPSC lines during self-renewal that lie along a fundamental axis of in vivo development. Distinct stable and dynamic transcriptional elements were revealed by decomposition of RNA-seq data in pluripotency and early lineage emergence. Stable differences within pluripotency predicted regional bias in the dynamics of neural differentiation that were also observed in large collections of hPSC lines. Using replicate human induced PSC (hiPSC) lines and paired adult tissue, we demonstrate that cells from individual humans expressed unique transcriptional signatures that were maintained throughout life. In addition, replicate hiPSC lines from one donor showed divergent expression phenotypes driven by distinct chromatin states. These stable transcriptional states are under both genetic and epigenetic control and predict bias in subsequent forebrain and hindbrain neural trajectories. These results define mechanisms controlling transcription in pluripotency to first establish human neural diversity. Data availability: GSE164055; https://nemoanalytics.org/p?l=KimEtAL2021&g=GBX2.Abstract Figure

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“…The analysis of somatic genetic mutations, together with DNA methylation marks, from blood DNA gave a substantially more accurate prediction of mortality, than either genetics or DNA methylation alone could provide 3 . Both DNA methylation and genotype are required to determine the pluripotency of induced stem cells 4 and their maturation capacity 5 . Germline genetic alterations cause changes in DNA methylation that ultimately dictates predisposition for disease 6,7,8 .…”

Section: Figurementioning

confidence: 99%

Accurate simultaneous sequencing of genetic and epigenetic bases in DNA

Füllgrabe

Gosal

Creed

et al. 2022

Preprint

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DNA comprises molecular information stored via genetic bases (G, C, T, A) and also epigenetic bases, principally 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Both genetic and epigenetic information are vital to our understanding of biology and disease states. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases typically fail to capture common C-to-T mutations or distinguish 5mC from 5hmC. Here, we present a single-base-resolution sequencing methodology that will simultaneously sequence complete genetics and complete epigenetics in a single workflow. The approach is non-destructive to DNA and provides a digital readout of bases, which we exemplify by simultaneous sequencing of G, C, T, A, 5mC and 5hmC; 6 letter sequencing. We demonstrate sequencing of human genomic DNA and also cell-free DNA taken from a blood sample of a cancer patient. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. We envisage it will be versatile across many applications in life sciences.

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Inherent genomic properties underlie the epigenomic heterogeneity of human induced pluripotent stem cells

Cited by 19 publications

References 87 publications

Controlled X‐chromosome dynamics defines meiotic potential of female mouse in vitro germ cells

Controlled X‐chromosome dynamics defines meiotic potential of female mouse in vitro germ cells

Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Accurate simultaneous sequencing of genetic and epigenetic bases in DNA

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