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- Andersson, Emil, et al.
(författare)
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CELLoGeNe - An energy landscape framework for logical networks controlling cell decisions
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:8
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Tidskriftsartikel (refereegranskat)abstract
- Experimental and computational efforts are constantly made to elucidate mechanisms controlling cell fate decisions during development and reprogramming. One powerful computational method is to consider cell commitment and reprogramming as movements in an energy landscape. Here, we develop Computation of Energy Landscapes of Logical Gene Networks (CELLoGeNe), which maps Boolean implementation of gene regulatory networks (GRNs) into energy landscapes. CELLoGeNe removes inadvertent symmetries in the energy landscapes normally arising from standard Boolean operators. Furthermore, CELLoGeNe provides tools to visualize and stochastically analyze the shapes of multi-dimensional energy landscapes corresponding to epigenetic landscapes for development and reprogramming. We demonstrate CELLoGeNe on two GRNs governing different aspects of induced pluripotent stem cells, identifying experimentally validated attractors and revealing potential reprogramming roadblocks. CELLoGeNe is a general framework that can be applied to various biological systems offering a broad picture of intracellular dynamics otherwise inaccessible with existing methods.
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| 2. |
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| 3. |
- Ruetz, Tyson, et al.
(författare)
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Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming
- 2017
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; , s. 9-805
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Tidskriftsartikel (refereegranskat)abstract
- Reprogramming of cellular identity using exogenous expression of transcription factors (TFs) is a powerful and exciting tool for tissue engineering, disease modeling, and regenerative medicine. However, generation of desired cell types using this approach is often plagued by inefficiency, slow conversion, and an inability to produce mature functional cells. Here, we show that expression of constitutively active SMAD2/3 significantly improves the efficiency of induced pluripotent stem cell (iPSC) generation by the Yamanaka factors. Mechanistically, SMAD3 interacts with reprogramming factors and co-activators and co-occupies OCT4 target loci during reprogramming. Unexpectedly, active SMAD2/3 also markedly enhances three other TF-mediated direct reprogramming conversions, from B cells to macrophages, myoblasts to adipocytes, and human fibroblasts to neurons, highlighting broad and general roles for SMAD2/3 as cell-reprogramming potentiators. Our results suggest that co-expression of active SMAD2/3 could enhance multiple types of TF-based cell identity conversion and therefore be a powerful tool for cellular engineering. Ruetz et al. show that constitutively active SMAD2/3 has a surprising ability to boost the efficiency of cell reprogramming both to iPSCs and across lineages and may therefore be a general factor that can enhance transcription-factor-mediated reprogramming in a variety of contexts.
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| 4. |
- Schöpp, Theresa, et al.
(författare)
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The DUF3715 domain has a conserved role in RNA-directed transposon silencing
- 2023
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Ingår i: RNA. - 1355-8382. ; 29:10, s. 1471-1480
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Tidskriftsartikel (refereegranskat)abstract
- RNA-directed transposon silencing operates in the mammalian soma and germline to safeguard genomic integrity. The piRNA pathway and the HUSH complex identify active transposons through recognition of their nascent transcripts, but mechanistic understanding of how these distinct pathways evolved is lacking. TASOR is an essential component of the HUSH complex. TASOR's DUF3715 domain adopts a pseudo-PARP structure and is required for transposon silencing in a manner independent of complex assembly. TEX15, an essential piRNA pathway factor, also contains the DUF3715 domain. Here, we show that TASOR's and TEX15's DUF3715 domain share extensive structural homology. We found that the DUF3715 domain arose in early eukaryotes and that in vertebrates it is restricted to TEX15, TASOR, and TASORB orthologues. While TASOR-like proteins are found throughout metazoa, TEX15 is vertebrate specific. The branching of TEX15 and TASOR-like DUF3715 domain likely occurred in early metazoan evolution. Remarkably, despite this vast evolutionary distance, the DUF3715 domain from divergent TEX15 sequences can functionally substitute for the same domain in TASOR and mediates transposon silencing. We have thus termed this domain of unknown function as the RNA-directed pseudo-PARP transposon silencing (RDTS) domain. In summary, we show an unexpected functional link between these critical transposon silencing pathways.
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