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Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE227830 | GEO | 2023/08/01

REPOSITORIES: GEO

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Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming (ATAC-Seq)

Project description:The SOX17 triple-mutant SOX17FNV is a more potent inducer of pluripotency than wild-type SOX2 for unknown features outside its DNA binding high mobility group box domain. Using an inducible reprogramming system, we verified that wild-type SOX17 is not capable to induce pluripotency but SOX17FNV outperforms SOX2 in mouse and human. In mature pluripotent stem cells, SOX17FNV can fully replace SOX2 without compromising self-renewal and pluripotency despite considerable sequence variation. Binding assays using full length proteins expressed in mammalian cells show that SOX17FNV and SOX17 co-bind OCT4 more tightly than SOX2 albeit with switched preferences for composite DNA motifs. Through the systematic analyses of domain deletions, we found that the N-terminus is dispensable for the reprogramming activity of SOX17FNV whilst the C-terminus encodes for essential as well as superfluous domains. Domains have non-additive and partially compensatory effects suggesting that versatile multivalent interaction drive transactivation and reprogramming. We define a minimal SOX17FNV (miniSOX) that can support reprogramming without loss in activity enabling payload reduction within reprogramming cassettes. The definition, functional evaluation and utilisation of potent effector domains that are optimised to pioneer cell fate transition will open up new avenues to enhance cellular reprogramming and stem cell engineering with synthetic transcription factors.

2023-08-01 | GSE227716 | GEO

Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming (RNA-Seq)

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Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming

Project description:Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming

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Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming (RNA-Seq)

Project description:Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming (RNA-Seq)

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Thinking out of the box to evaluate the performance of engineered SOX17 in pluripotency reprogramming (ATAC-Seq)

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An engineered Sox17 induces somatic to neural stem cell fate transitions independently from pluripotency reprogramming.

Project description:Advanced strategies to interconvert cell types provide promising avenues to model cellular pathologies and to develop therapies for neurological disorders. Yet, methods to directly transdifferentiate somatic cells into multipotent induced neural stem cells (iNSCs) are slow and inefficient, and it is unclear whether cells pass through a pluripotent state with full epigenetic reset. We report iNSC reprogramming from embryonic and aged mouse fibroblasts as well as from human blood using an engineered Sox17 (eSox17FNV). eSox17FNV efficiently drives iNSC reprogramming while Sox2 or Sox17 fail. eSox17FNV acquires the capacity to bind different protein partners on regulatory DNA to scan the genome more efficiently and has a more potent transactivation domain than Sox2. Lineage tracing and time-resolved transcriptomics show that emerging iNSCs do not transit through a pluripotent state. Our work distinguishes lineage from pluripotency reprogramming with the potential to generate more authentic cell models for aging-associated neurodegenerative diseases.

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An engineered Sox17 induces somatic to neural stem cell fate transition independently from pluripotency reprogramming

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-07-19 | GSE195556 | GEO

Evaluation of the determinants for improved pluripotency induction and maintenance by engineered SOX17.

Project description:An engineered SOX17 variant with point mutations within its DNA binding domain termed SOX17FNV is a more potent pluripotency inducer than SOX2, yet the underlying mechanism remains unclear. Although wild-type SOX17 was incapable of inducing pluripotency, SOX17FNV outperformed SOX2 in mouse and human pluripotency reprogramming. In embryonic stem cells, SOX17FNV could replace SOX2 to maintain pluripotency despite considerable sequence differences and upregulated genes expressed in cleavage-stage embryos. Mechanistically, SOX17FNV co-bound OCT4 more cooperatively than SOX2 in the context of the canonical SoxOct DNA element. SOX2, SOX17, and SOX17FNV were all able to bind nucleosome core particles in vitro, which is a prerequisite for pioneer transcription factors. Experiments using purified proteins and in cellular contexts showed that SOX17 variants phase-separated more efficiently than SOX2, suggesting an enhanced ability to self-organise. Systematic deletion analyses showed that the N-terminus of SOX17FNV was dispensable for its reprogramming activity. However, the C-terminus encodes essential domains indicating multivalent interactions that drive transactivation and reprogramming. We defined a minimal SOX17FNV (miniSOX) that can support reprogramming with high activity, reducing the payload of reprogramming cassettes. This study uncovers the mechanisms behind SOX17FNV-induced pluripotency and establishes engineered SOX factors as powerful cell engineering tools.

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Project description:Forkhead box (Fox) transcription factors play important roles in mammalian development and disease. However, their function in mouse somatic cell reprogramming remains unclear. Here, we report that FoxD subfamily and FoxG1 accelerate induced pluripotent stem cells (iPSCs) generation from mouse fibroblasts as early as day4 while FoxA and FoxO subfamily impede this process obviously. More importantly, FoxD3, FoxD4 and FoxG1 can replace Oct4 respectively and generate iPSCs with germline transmission together with Sox2 and Klf4. On the contrary, FoxO6 almost totally blocks reprogramming through inhibiting cell proliferation, suppressing the expression of pluripotent genes and hindering the process of mesenchymal to epithelial transition (MET). Thus, our study uncovers unexpected roles of Fox transcription factors in reprogramming and offers new insights into cell fate transition.

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