TY - JOUR
T1 - Attenuating iPSC reprogramming stress with dominant-negative BET peptides
AU - Hossain, Md Emon
AU - Cevallos, Ricardo Raul
AU - Zhang, Ruowen
AU - Hu, Kejin
N1 - Funding Information:
This work was supported by a fund from National Institutes of Health (NIH) (R01GM127411) to K.H. We appreciate the infrastructure and staff support from UAB Comprehensive Flow Cytometry Core, the UAB Research Computing unit, UAB Comparative Pathology Laboratory, and UAB Animal Resources Program. We thank Novogene and Genewiz for their sequencing services, and Cell Line Genetics (Madison, Wisconsin) for karyotyping. We thank Drs. Tim Townes and Kevin Pawlik for their fluorescence microscope. We thank Dr. Louise Chow for critical reading of this manuscript before submission. We thank Dr. Jianqing Zhang from UAB NanoString Laboratory for his technical help in nCounter analyses. Conceptualization, K.H.; Methodology, K.H. M.E.H. R.R.C. R.Z.; Investigation, K.H. M.E.H. R.R.C. R.Z.; Validation, K.H. M.E.H. R.R.C. R.Z.; Formal Analysis, K.H. M.E.H. R.R.C.; Writing – Original Draft, K.H.; Writing – Review and Editing, K.H. M.E.H. R.R.C. R.Z.; Resources, K.H.; Data Curation, K.H. R.R.C.; Visualization, K.H. R.R.C.; Supervision, K.H.; Funding Acquisition, K.H. All authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. We support inclusive, diverse, and equitable conduct of research.
Funding Information:
This work was supported by a fund from National Institutes of Health (NIH) ( R01GM127411 ) to K.H. We appreciate the infrastructure and staff support from UAB Comprehensive Flow Cytometry Core, the UAB Research Computing unit , UAB Comparative Pathology Laboratory , and UAB Animal Resources Program . We thank Novogene and Genewiz for their sequencing services, and Cell Line Genetics (Madison, Wisconsin) for karyotyping. We thank Drs. Tim Townes and Kevin Pawlik for their fluorescence microscope. We thank Dr. Louise Chow for critical reading of this manuscript before submission. We thank Dr. Jianqing Zhang from UAB NanoString Laboratory for his technical help in nCounter analyses .
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/1/20
Y1 - 2023/1/20
N2 - 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.
AB - 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.
KW - Peptides
KW - Protein
KW - Stem cell plasticity
KW - Stem cells research
UR - http://www.scopus.com/inward/record.url?scp=85146179012&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.105889
DO - 10.1016/j.isci.2022.105889
M3 - Article
AN - SCOPUS:85146179012
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 1
M1 - 105889
ER -