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Identifying novel regulators of human pluripotency and embryogenesis

Lea, Rebecca Anne; (2021) Identifying novel regulators of human pluripotency and embryogenesis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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In preimplantation development, the pluripotent epiblast is the precursor of all foetal tissues and of human embryonic stem cells (hESCs). Investigating the regulatory mechanisms that underpin human pluripotency is therefore vital to understand human embryogenesis and to improve in vitro models of human pluripotency. However, our current knowledge of the transcriptional regulation of human pluripotency is incomplete. In particular, various regulators identified through studies in the mouse display non-conserved expression or function in the human embryo. To explore how such proteins might be involved in the regulation of human pluripotency, I identified a number of transcription factors that are enriched in the human epiblast and expressed specifically in hESCs cultured under naïve, but not primed, pluripotency conditions. Through analysis of expression in both naïve hESCs and the developing human blastocyst, I determined that KLF17 is a promising candidate pluripotency regulator. I therefore performed gain- and loss-of-function analyses to elucidate the function of KLF17 in hESCs. Through ectopic expression of KLF17, I found that it is sufficient to upregulate the expression of a number of naïve hESC-associated genes in primed conditions and to drive transgene-mediated resetting of primed to naïve pluripotency under appropriate culture conditions. However, a CRISPR-Cas9-mediated null mutation of KLF17 revealed that it is not required for naïve pluripotency acquisition or maintenance in vitro. By transcriptome analysis of KLF17-null mutant hESCs during resetting, I identified possible compensatory mechanisms including upregulated expression of paralogous genes and the impact of exogenous WNT inhibition. In all, this work shows a role for KLF17 in establishing naïve pluripotency, but that it is not strictly necessary for generating naïve hESCs. I therefore suggest that the function of KLF17 is to promote a naïve pluripotent phenotype but that under standard conditions, parallel mechanisms exist and are able to compensate in the absence of KLF17.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Identifying novel regulators of human pluripotency and embryogenesis
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10129872
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