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Changing POU dimerization preferences converts Oct6 into a pluripotency inducer

Jerabek, Stepan, Ng, Calista KL, Wu, Guangming, Arauzo‐Bravo, Marcos J, Kim, Kee‐Pyo, Esch, Daniel, Malik, Vikas, Chen, Yanpu, Velychko, Sergiy, MacCarthy, Caitlin M, Yang, Xiaoxiao, Cojocaru, Vlad, Schöler, Hans R, Jauch, Ralf·2017·The EMBO Reports
DOI 10.15252/embr.201642958PMC PMC5286379
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Abstract

The transcription factor Oct4 is a core component of molecular cocktails inducing pluripotent stem cells (iPSCs), while other members of the POU family cannot replace Oct4 with comparable efficiency. Rather, group III POU factors such as Oct6 induce neural lineages. Here, we sought to identify molecular features determining the differential DNA‐binding and reprogramming activity of Oct4 and Oct6. In enhancers of pluripotency genes, Oct4 cooperates with Sox2 on heterodimeric SoxOct elements. By re‐analyzing ChIP‐Seq data and performing dimerization assays, we found that Oct6 homodimerizes on palindromic OctOct more cooperatively and more stably than Oct4. Using structural and biochemical analyses, we identified a single amino acid directing binding to the respective DNA elements. A change in this amino acid decreases the ability of Oct4 to generate iPSCs, while the reverse mutation in Oct6 does not augment its reprogramming activity. Yet, with two additional amino acid exchanges, Oct6 acquires the ability to generate iPSCs and maintain pluripotency. Together, we demonstrate that cell type‐specific POU factor function is determined by select residues that affect DNA‐dependent dimerization.

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  • OCT4 binds regulatory regions of pluripotency network genes to create an autoregulatory pluripotency network.

    “Third, OCT4 binds regulatory regions of pluripotency network genes to create an autoregulatory pluripotency network 42,43 .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [42]

    The Introduction (page unavailable) says genome-wide studies identified Sox2–Oct4 binding elements in enhancers of pluripotency-related genes, including Pou5f1 (the Oct4 gene), Nanog, and Utf1. This supports binding to regulatory regions, including one associated with Oct4 itself, but the paper does not establish that this binding creates an autoregulatory pluripotency network. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • NANOG shares 90% of the OCT4 and SOX2 binding regions.

    “One of the most studied factors besides OKSM is NANOG, a transcription factor belonging to the pluripotency network 59 and sharing 90% of the OCT4 and SOX2 binding regions 42 .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [42]

    The Results section on enhancer signature motifs discusses OCT4–SOX2 binding but does not measure NANOG binding-region overlap. Searches for NANOG with “90%” and for shared OCT4–SOX2 binding sites found no passage supporting the stated percentage; the References section mentions NANOG only in a cited title. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • KLF4 and MYC are believed to drive the first wave of transcriptional activation.

    “and KLF4 (as well as MYC, described in detail below) is believed to drive the first wave of transcriptional activation 42 .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [42]

    The Introduction (page unavailable) identifies Klf4 and c-Myc as reprogramming factors, but does not say they drive a first wave of transcriptional activation. Searches for that phrase and for early transcriptional activation found no passage in our copy addressing the claimed timing or role. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

  • OCT4 and SOX2 are mainly responsible for increasing chromatin accessibility during full iPS cell reprogramming.

    “OCT4 and SOX2 are mainly responsible for increasing chromatin accessibility during full iPS cell reprogramming, and KLF4 (as well as MYC, described in detail below) is believed to drive the first wave of transcriptional activation 42 .”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [42]

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Metadata

Authors
Jerabek, S., Ng, C. K., Wu, G., Arauzo‐Bravo, M. J., Kim, K., Esch, D., Malik, V., Chen, Y., Velychko, S., MacCarthy, C. M., Yang, X., Cojocaru, V., Schöler, H. R., & Jauch, R.
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2016-12-22
Volume
18
Issue
2
Pages
319-333
ISSN
  • 1469-221X
  • 1469-3178
DOI
10.15252/embr.201642958
PMC
PMC5286379
Cited by
42
References
3
Language
en
Licence
Funders
  • Ministry of Science and Technology of the People's Republic of China (2013DFE33080, 2016YFA0100700)
  • National Natural Science Foundation of China (31471238)
  • Chinese Academy of Sciences
  • Guangdong Science and Technology Department (2014B030301058, 2016A050503038)
  • Max Planck Society
  • Deutsche Forschungsgemeinschaft (CO 975/1‐1)
  • Cells in Motion (CiM) Graduate School
  • International Max Planck Research School—Molecular Biomedicine
  • University of the Chinese Academy of Sciences (UCAS) and The World Academy of Science
  • Partnership for Advanced Computing in Europe AISBL

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