@article{25612169d5db4feda3ba57c2634f0a4d,
title = "Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells",
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.",
author = "Missinato, {Maria A.} and Sean Murphy and Michaela Lynott and Yu, {Michael S.} and Ana{\"i}s Kervadec and Chang, {Yu Ling} and Suraj Kannan and Mafalda Loreti and Christopher Lee and Prashila Amatya and Hiroshi Tanaka and Huang, {Chun Teng} and Puri, {Pier Lorenzo} and Chulan Kwon and Adams, {Peter D.} and Li Qian and Alessandra Sacco and Peter Andersen and Colas, {Alexandre R.}",
note = "Funding Information: This work was supported by grants DISC2-10110 (California Institute for Regenerative Medicine), R01 HL153645, R01 HL148827, R01 HL149992, R01 AG071464 (National Institutes of Health), and SBP institutional support to A.R.C. Sanford Burnham Prebys Shared Resources are supported by an NCI Cancer Center Support Grant (P30 CA030199). We thank Kirsten Jepsen (UCSD IGM Genomic Core Facility) for assistance with the ChIP-seq experiments; Allen Wang and Sebastian Preissl (UCSD CMME) for assistance with the scATAC-seq experiments; Nadan Wang and Michelle Leppo (JHU SOM) for assistance with mouse surgeries and echo-guided injections; Luca Caputo, Haley Vaseghi, and Li Wang for kindly sharing reagents and instruments; and Sean Spiering, Eleanor Kim, and Josiah Punay for excellent technical support. Funding Information: This work was supported by grants DISC2-10110 (California Institute for Regenerative Medicine), R01 HL153645, R01 HL148827, R01 HL149992, R01 AG071464 (National Institutes of Health), and SBP institutional support to A.R.C. Sanford Burnham Prebys Shared Resources are supported by an NCI Cancer Center Support Grant (P30 CA030199). We thank Kirsten Jepsen (UCSD IGM Genomic Core Facility) for assistance with the ChIP-seq experiments; Allen Wang and Sebastian Preissl (UCSD CMME) for assistance with the scATAC-seq experiments; Nadan Wang and Michelle Leppo (JHU SOM) for assistance with mouse surgeries and echo-guided injections; Luca Caputo, Haley Vaseghi, and Li Wang for kindly sharing reagents and instruments; and Sean Spiering, Eleanor Kim, and Josiah Punay for excellent technical support. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = dec,
doi = "10.1038/s41467-023-37256-8",
language = "English (US)",
volume = "14",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}