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Disruption of RING and PHD Domains of TRIM28 Evokes Differentiation in Human iPSCs
Sylwia Mazurek1,2, Urszula Oleksiewicz1,2, Patrycja Czerwińska1,2
1Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 61-701 Poznan, Poland.
Abstract:
TRIM28, a multi-domain protein, is crucial in the development of mouse embryos and the maintenance of embryonic stem cells' (ESC) self-renewal potential. As the epigenetic factor modulating chromatin structure, TRIM28 regulates the expression of numerous genes and is associated with progression and poor prognosis in many types of cancer. Because of many similarities between highly dedifferentiated cancer cells and normal pluripotent stem cells, we applied human induced pluripotent stem cells (hiPSC) as a model for stemness studies. For the first time in hiPSC, we analyzed the function of individual TRIM28 domains. Here we demonstrate the essential role of a really interesting new gene (RING) domain and plant homeodomain (PHD) in regulating pluripotency maintenance and self-renewal capacity of hiPSC. Our data indicate that mutation within the RING or PHD domain leads to the loss of stem cell phenotypes and downregulation of the FGF signaling. Moreover, impairment of RING or PHD domain results in decreased proliferation and impedes embryoid body formation. In opposition to previous data indicating the impact of phosphorylation on TRIM28 function, our data suggest that TRIM28 phosphorylation does not significantly affect the pluripotency and self-renewal maintenance of hiPSC. Of note, iPSC with disrupted RING and PHD functions display downregulation of genes associated with tumor metastasis, which are considered important targets in cancer treatment. Our data suggest the potential use of RING and PHD domains of TRIM28 as targets in cancer therapy.
Insights
The RING and PHD domains of TRIM28 are essential for maintaining stem cell pluripotency and self-renewal. Disrupting these domains in human induced pluripotent stem cells (hiPSC) may offer new cancer therapy targets.
Area of Science:
- Epigenetics and Stem Cell Biology
- Cancer Biology
Background:
- * Tripartite motif-containing protein 28 (TRIM28) is a key epigenetic regulator vital for embryonic development and stem cell self-renewal.
- * TRIM28's role in cancer progression highlights similarities between cancer cells and pluripotent stem cells.
- * Human induced pluripotent stem cells (hiPSC) serve as a model to study stemness and TRIM28 function.
Purpose of the Study:
- * To investigate the function of individual TRIM28 domains in hiPSC for the first time.
- * To elucidate the role of TRIM28 in maintaining pluripotency and self-renewal capacity.
- * To explore the therapeutic potential of TRIM28 domains in cancer treatment.
Main Methods:
- * Functional analysis of individual TRIM28 domains (RING and PHD) in hiPSC.
- * Assessment of stem cell phenotypes, FGF signaling, proliferation, and embryoid body formation upon domain mutation.
- * Investigation of TRIM28 phosphorylation's effect on pluripotency and self-renewal.
Main Results:
- * The Really Interesting New Gene (RING) and Plant Homeodomain (PHD) domains are critical for hiPSC pluripotency and self-renewal.
- * Mutations in RING or PHD domains abolish stem cell phenotypes, downregulate FGF signaling, reduce proliferation, and impede embryoid body formation.
- * TRIM28 phosphorylation does not significantly impact pluripotency or self-renewal in hiPSC.
- * Disruption of RING and PHD domains leads to downregulation of metastasis-associated genes in hiPSC.
Conclusions:
- * The RING and PHD domains of TRIM28 are essential for maintaining hiPSC pluripotency and self-renewal.
- * TRIM28's RING and PHD domains represent potential therapeutic targets for cancer treatment, particularly for metastasis.
- * Further research into TRIM28's role in cancer could lead to novel anti-cancer strategies.
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