Interplay Between Pioneer Transcription Factors and Epigenetic Modifiers in Cell Reprogramming

Overview

Journal Regen Ther

Date 2025 Jan 21

PMID 39834592

Authors

Gerardo Mirizio

Samuel Sampson

Makiko Iwafuchi

Affiliations

Soon will be listed here.

Abstract

The generation of induced pluripotent stem cells (iPSCs) from differentiated somatic cells by Yamanaka factors, including pioneer transcription factors (TFs), has greatly reshaped our traditional understanding of cell plasticity and demonstrated the remarkable potential of pioneer TFs. In addition to iPSC reprogramming, pioneer TFs are pivotal in direct reprogramming or transdifferentiation where somatic cells are converted into different cell types without passing through a pluripotent state. Pioneer TFs initiate a reprogramming process through chromatin opening, thereby establishing competence for new gene regulatory programs. The action of pioneer TFs is both influenced by and exerts influence on epigenetic regulation. Despite significant advances, many direct reprogramming processes remain inefficient, which limits their reliability for clinical applications. In this review, we discuss the molecular mechanisms underlying pioneer TF-driven reprogramming, with a focus on their interactions with epigenetic modifiers, including Polycomb repressive complexes (PRCs), nucleosome remodeling and deacetylase (NuRD) complexes, and the DNA methylation machinery. A deeper understanding of the dynamic interplay between pioneer TFs and epigenetic modifiers will be essential for advancing reprogramming technologies and unlocking their full clinical potential.

References

MacCarthy C, Wu G, Malik V, Menuchin-Lasowski Y, Velychko T, Keshet G . Highly cooperative chimeric super-SOX induces naive pluripotency across species. Cell Stem Cell. 2023; 31(1):127-147.e9. DOI: 10.1016/j.stem.2023.11.010. View

Baubec T, Ivanek R, Lienert F, Schubeler D . Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell. 2013; 153(2):480-92. DOI: 10.1016/j.cell.2013.03.011. View

Whyte W, Bilodeau S, Orlando D, Hoke H, Frampton G, Foster C . Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature. 2012; 482(7384):221-5. PMC: 4144424. DOI: 10.1038/nature10805. View

Dos Santos R, Tosti L, Radzisheuskaya A, Caballero I, Kaji K, Hendrich B . MBD3/NuRD facilitates induction of pluripotency in a context-dependent manner. Cell Stem Cell. 2014; 15(1):102-10. PMC: 4082719. DOI: 10.1016/j.stem.2014.04.019. View

Zhang Y, Zhang D, Li Q, Liang J, Sun L, Yi X . Nucleation of DNA repair factors by FOXA1 links DNA demethylation to transcriptional pioneering. Nat Genet. 2016; 48(9):1003-13. DOI: 10.1038/ng.3635. View

Buganim Y, Faddah D, Cheng A, Itskovich E, Markoulaki S, Ganz K . Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell. 2012; 150(6):1209-22. PMC: 3457656. DOI: 10.1016/j.cell.2012.08.023. View

Horisawa K, Suzuki A . Direct cell-fate conversion of somatic cells: Toward regenerative medicine and industries. Proc Jpn Acad Ser B Phys Biol Sci. 2020; 96(4):131-158. PMC: 7247973. DOI: 10.2183/pjab.96.012. View

Suelves M, Carrio E, Nunez-Alvarez Y, Peinado M . DNA methylation dynamics in cellular commitment and differentiation. Brief Funct Genomics. 2016; 15(6):443-453. DOI: 10.1093/bfgp/elw017. View

Li R, Liang J, Ni S, Zhou T, Qing X, Li H . A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell. 2010; 7(1):51-63. DOI: 10.1016/j.stem.2010.04.014. View

10.

Matsui S, Granitto M, Buckley M, Ludwig K, Koigi S, Shiley J . Pioneer and PRDM transcription factors coordinate bivalent epigenetic states to safeguard cell fate. Mol Cell. 2024; 84(3):476-489.e10. PMC: 10872272. DOI: 10.1016/j.molcel.2023.12.007. View

11.

Yang J, Bashkenova N, Zang R, Huang X, Wang J . The roles of TET family proteins in development and stem cells. Development. 2020; 147(2). PMC: 6983710. DOI: 10.1242/dev.183129. View

12.

Wang L, Liu Z, Yin C, Asfour H, Chen O, Li Y . Stoichiometry of Gata4, Mef2c, and Tbx5 influences the efficiency and quality of induced cardiac myocyte reprogramming. Circ Res. 2014; 116(2):237-44. PMC: 4299697. DOI: 10.1161/CIRCRESAHA.116.305547. View

13.

Li J, Wu X, Ke J, Lee M, Lan Q, Li J . TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation. Nat Commun. 2022; 13(1):3907. PMC: 9263144. DOI: 10.1038/s41467-022-31611-x. View

14.

Tanay A, ODonnell A, Damelin M, Bestor T . Hyperconserved CpG domains underlie Polycomb-binding sites. Proc Natl Acad Sci U S A. 2007; 104(13):5521-6. PMC: 1838490. DOI: 10.1073/pnas.0609746104. View

15.

Jaenisch R, Young R . Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell. 2008; 132(4):567-82. PMC: 4142810. DOI: 10.1016/j.cell.2008.01.015. View

16.

Su Z, Niu W, Liu M, Zou Y, Zhang C . In vivo conversion of astrocytes to neurons in the injured adult spinal cord. Nat Commun. 2014; 5:3338. PMC: 3966078. DOI: 10.1038/ncomms4338. View

17.

Horisawa K, Udono M, Ueno K, Ohkawa Y, Nagasaki M, Sekiya S . The Dynamics of Transcriptional Activation by Hepatic Reprogramming Factors. Mol Cell. 2020; 79(4):660-676.e8. DOI: 10.1016/j.molcel.2020.07.012. View

18.

Costa Y, Ding J, Theunissen T, Faiola F, Hore T, Shliaha P . NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature. 2013; 495(7441):370-4. PMC: 3606645. DOI: 10.1038/nature11925. View

19.

Rais Y, Zviran A, Geula S, Gafni O, Chomsky E, Viukov S . Deterministic direct reprogramming of somatic cells to pluripotency. Nature. 2013; 502(7469):65-70. DOI: 10.1038/nature12587. View

20.

Kim M, Costello J . DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017; 49(4):e322. PMC: 6130213. DOI: 10.1038/emm.2017.10. View