Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells

Maria A. Missinato, Sean Murphy, Michaela Lynott, Michael S. Yu, Anaïs Kervadec, Yu-Ling Chang, Suraj Kannan, Mafalda Loreti, Christopher Lee, Prashila Amatya, Hiroshi Tanaka, Chun-Teng Huang, Pier Lorenzo Puri, Chulan Kwon, Peter D. Adams, Li Qian, Alessandra Sacco, Peter Andersen () and Alexandre R. Colas ()
Additional contact information
Maria A. Missinato: Sanford Burnham Prebys Medical Discovery Institute
Sean Murphy: Johns Hopkins University School of Medicine
Michaela Lynott: Sanford Burnham Prebys Medical Discovery Institute
Michael S. Yu: Sanford Burnham Prebys Medical Discovery Institute
Anaïs Kervadec: Sanford Burnham Prebys Medical Discovery Institute
Yu-Ling Chang: Sanford Burnham Prebys Medical Discovery Institute
Suraj Kannan: Johns Hopkins University School of Medicine
Mafalda Loreti: Sanford Burnham Prebys Medical Discovery Institute
Christopher Lee: Sanford Burnham Prebys Medical Discovery Institute
Prashila Amatya: Sanford Burnham Prebys Medical Discovery Institute
Hiroshi Tanaka: Sanford Burnham Prebys Medical Discovery Institute
Chun-Teng Huang: Viral Vector Core Facility Sanford Burnham Prebys Medical Discovery Institute
Pier Lorenzo Puri: Sanford Burnham Prebys Medical Discovery Institute
Chulan Kwon: Johns Hopkins University School of Medicine
Peter D. Adams: Sanford Burnham Prebys Medical Discovery Institute
Li Qian: University of North Carolina at Chapel Hill
Alessandra Sacco: Sanford Burnham Prebys Medical Discovery Institute
Peter Andersen: Johns Hopkins University School of Medicine
Alexandre R. Colas: Sanford Burnham Prebys Medical Discovery Institute

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) - our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) - our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207 [AJSZ]) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners. Mechanistically, our integrated multi-omics approach (ChIP, ATAC and RNA-seq) revealed that AJSZ oppose cell fate reprogramming by 1) - maintaining chromatin enriched for reprogramming TF motifs in a closed state and 2) - downregulating genes required for reprogramming. Finally, KD of AJSZ in combination with MGT overexpression, significantly reduced scar size and improved heart function by 50%, as compared to MGT alone post-myocardial infarction. Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.

Date: 2023
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DOI: 10.1038/s41467-023-37256-8

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