The role of SOCS3 in nuclear reprogramming and na��ve pluripotency network integration
| Autor: | Hladkou, Siarhei |
|---|---|
| Rok vydání: | 2021 |
| Předmět: | |
| DOI: | 10.17863/cam.75010 |
| Popis: | Survival and persistence of live matter requires certain flexibility to allow multiple adaptations, yet it is grounded on orderly and stringent regulation of its important functions. An astounding example of natural planning is given by mammalian embryological development where a sophisticated specification program enclosed in a single cell is resolved into a diversity of tissues in a mature organism. Tracing back the developmental timeline is a way to deconvolute advanced biological properties that cells acquire through a series of hierarchical differentiation decisions. One of the primary unspecified states spanning a short period between conception and functional commitment of the cell is known as pluripotency. Pluripotency is the ability of a cell to give rise to the derivatives of the three germ layers and germ cells during differentiation. Naturally, pluripotency is restricted to the early embryo only and represented by two morphologically, physiologically and epigenetically sequential stages ��� na��ve (embryonic stem cells, or ESCs) and primed (post-implantation epiblast stem cells, or EpiSCc). Revolutionary technologies of nuclear reprogramming are now able to artificially revert developmental vector and direct differentiated cells towards na��ve pluripotency. Reprogrammed cells not only come as a useful object for fundamental research but also as a flexible biological tool for regenerative therapies. Currently reprogramming is moderately efficient, however reliable and safe medical strategies require decent understanding of the physiological and genetic networks underpinning cell identity change. Importantly, the primed pluripotent cell can be reprogrammed too allowing to focus on the first and often subtle cell identity transitions that cells adopt. In my project, I have performed a forward genome-wide CRISPR-gRNA knockout screen to identify genes working as barriers for reprogramming from EpiSCs to ESCs. Having assembled a comprehensive lentiviral library and established a tractable cell system to target the mouse genome, I screened EpiSCs in the reprogramming setup which allowed selection of effective reprogramming antagonists. Here I discover the JAK/STAT3 pathway regulator Socs3 as a key screen hit and describe this gene as a self-sufficient and powerful roadblock between the pluripotent identities. I show how a spectrum of its attenuated activities displayed in na��ve pluripotent and reprogramming cells may be functionally linked to reinforced pluripotency. Exploring the interplay between JAK/STAT3 pathway and other major na��ve pluripotency genes across na��ve, primed and non-pluripotent cell contexts reveals partially conservative mode of action of SOCS3. I demonstrate how SOCS3 may integrate external signalling with endogenous core pluripotency factors and by thereby feed in the na��ve circuity supporting it and instructing its establishment. This work helps understand the mechanisms behind reprogramming and biology of pluripotency which potentially can provide insights into consolidated and robust medical cell technologies. The Darwin Trust of Edinburgh and Cambridge Trust |
| Databáze: | OpenAIRE |
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