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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 Hua, 2023. "Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37256-8
    DOI: 10.1038/s41467-023-37256-8
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    References listed on IDEAS

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    1. Ralph Stadhouders & Guillaume J. Filion & Thomas Graf, 2019. "Transcription factors and 3D genome conformation in cell-fate decisions," Nature, Nature, vol. 569(7756), pages 345-354, May.
    2. Naoto Muraoka & Kaori Nara & Fumiya Tamura & Hidenori Kojima & Hiroyuki Yamakawa & Taketaro Sadahiro & Kazutaka Miyamoto & Mari Isomi & Sho Haginiwa & Hidenori Tani & Shota Kurotsu & Rina Osakabe & Sa, 2019. "Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Ziqing Liu & Li Wang & Joshua D. Welch & Hong Ma & Yang Zhou & Haley Ruth Vaseghi & Shuo Yu & Joseph Blake Wall & Sahar Alimohamadi & Michael Zheng & Chaoying Yin & Weining Shen & Jan F. Prins & Jiand, 2017. "Single-cell transcriptomics reconstructs fate conversion from fibroblast to cardiomyocyte," Nature, Nature, vol. 551(7678), pages 100-104, November.
    4. Zhiping P. Pang & Nan Yang & Thomas Vierbuchen & Austin Ostermeier & Daniel R. Fuentes & Troy Q. Yang & Ami Citri & Vittorio Sebastiano & Samuele Marro & Thomas C. Südhof & Marius Wernig, 2011. "Induction of human neuronal cells by defined transcription factors," Nature, Nature, vol. 476(7359), pages 220-223, August.
    5. Li Qian & Yu Huang & C. Ian Spencer & Amy Foley & Vasanth Vedantham & Lei Liu & Simon J. Conway & Ji-dong Fu & Deepak Srivastava, 2012. "In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes," Nature, Nature, vol. 485(7400), pages 593-598, May.
    6. Salah Mahmoudi & Elena Mancini & Lucy Xu & Alessandra Moore & Fereshteh Jahanbani & Katja Hebestreit & Rajini Srinivasan & Xiyan Li & Keerthana Devarajan & Laurie Prélot & Cheen Euong Ang & Yohei Shib, 2019. "Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing," Nature, Nature, vol. 574(7779), pages 553-558, October.
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    1. Xingting Guo & Chenhui Wang & Yongchao Zhang & Ruxue Wei & Rongwen Xi, 2024. "Cell-fate conversion of intestinal cells in adult Drosophila midgut by depleting a single transcription factor," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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