Details

Autor(en) / Beteiligte

• Missinato, Maria A.
• Murphy, Sean
• Lynott, Michaela
• Yu, Michael S.
• Kervadec, Anaïs
• Chang, Yu-Ling
• Kannan, Suraj
• Loreti, Mafalda
• Lee, Christopher
• Amatya, Prashila
• Tanaka, Hiroshi
• Huang, Chun-Teng
• Puri, Pier Lorenzo
• Kwon, Chulan
• Adams, Peter D.
• Qian, Li
• Sacco, Alessandra
• Andersen, Peter
• Colas, Alexandre R.

Titel

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

Ist Teil von

• Nature communications, 2023-03, Vol.14 (1), p.1709-1709, Article 1709

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Transdifferentiation has been proposed as an approach for regenerative medicine, but the mechanisms that safeguard cell identity are not well established. Here they identify transcription factors that oppose transdifferentiation and show that knockdown of these genes improves recovery after myocardial infarction.