Fernandes, Liane P.;
(2023)
Using ZFP819 to investigate the co-option of repetitive elements to regulate gene networks.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Repetitive elements (REs) constitute over fifty percent of mammalian genomes and include the rapidly evolving satellite DNA arrays. Expansion of REs is prevented by sequence-specific KRAB zinc finger proteins (KZFPs) that recruit TRIM28 and SETDB1 for epigenetic silencing. While they pose a threat to host genome integrity, REs are also recognized as important regulatory elements. We hypothesize that co-evolution with the host genome has led REs and their cognate KZFPs to be co-opted to regulate host gene networks. This thesis addresses this hypothesis by focusing on the murine KZFP, ZFP819. ZFP819 specifically targets ZP3AR, a satellite repeat clustered across megabase regions of chromosomes 5 and 7. The ZP3AR array on chromosome 7 barcodes and designates the Zscan4 gene cluster, which encodes ZSCAN4, a master regulator of totipotency. Depleting Zfp819 in mouse embryonic stem cells (mESCs) causes them to transition to a 2-cell (2C)-like state, whereby the ZP3AR array switches from a poised to an active enhancer state. This is accompanied by a global erosion of heterochromatin roadblocks, which we link to decreased SETDB1 protein stability, and the activation of genome-wide enhancers, resulting in the transcription of active LINE1 elements and impaired differentiation. We propose that ZFP819 and TRIM28-mediated epigenetic silencing is required to close chromatin across Zscan4 and promote exit from totipotency. A breakdown in this epigenetic program can lead to unwarranted activation of the 2C gene network and impaired SETDB1-mediated heterochromatin formation during early development. This could lead to genomic instability associated with malignancies and autoimmunity in somatic tissues. We hypothesize that satellite DNA arrays are platforms to control developmental fate transitions by barcoding and switching off master transcription factor genes, thereby safeguarding genome integrity and cellular identity.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Using ZFP819 to investigate the co-option of repetitive elements to regulate gene networks |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. 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 > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10167586 |
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