Attenuating iPSC reprogramming stress with dominant-negative BET peptides

Md Emon Hossain; Ricardo Raul Cevallos; Ruowen Zhang; Kejin Hu

doi:10.1016/j.isci.2022.105889

Attenuating iPSC reprogramming stress with dominant-negative BET peptides

iScience. 2022 Dec 28;26(1):105889. doi: 10.1016/j.isci.2022.105889. eCollection 2023 Jan 20.

Authors

Md Emon Hossain¹, Ricardo Raul Cevallos¹, Ruowen Zhang¹, Kejin Hu¹

Affiliation

¹ Department of Biochemistry and Molecular Genetics, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Abstract

Generation of induced pluripotent stem cells (iPSCs) is inefficient and stochastic. The underlying causes for these deficiencies are elusive. Here, we showed that the reprogramming factors (OCT4, SOX2, and KLF4, collectively OSK) elicit dramatic reprogramming stress even without the pro-oncogene MYC including massive transcriptional turbulence, massive and random deregulation of stress-response genes, cell cycle impairment, downregulation of mitotic genes, illegitimate reprogramming, and cytotoxicity. The conserved dominant-negative (DN) peptides of the three ubiquitous human bromodomain and extraterminal (BET) proteins enhanced iPSC reprogramming and mitigated all the reprogramming stresses mentioned above. The concept of reprogramming stress developed here affords an alternative avenue to understanding and improving iPSC reprogramming. These DN BET fragments target a similar set of the genes as the BET chemical inhibitors do, indicating a distinct approach to targeting BET proteins.

Keywords: Peptides; Protein; Stem cell plasticity; Stem cells research.

Abstract

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