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, Alexandre R. Colas

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article number1709
JournalNature communications
Issue number1
StatePublished - Dec 2023

ASJC Scopus subject areas

  • General Physics and Astronomy
  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology


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