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Inheritance of OCT4 predetermines fate choice in human embryonic stem cells

Samuel C. Wolff, Raluca Dumitru, Kasia M. Kedziora, Cierra D. Dungee, Tarek M. Zikry, Rachel A. Haggerty, JrGang Cheng, Adriana S. Beltran, Jeremy E. Purvis

Preprint posted on January 26, 2018 https://www.biorxiv.org/content/early/2018/01/26/137299

Does protein allocation at cell division impact cell fate? Asymmetric inheritance of the pluripotency-associated factor OCT4 during human embryonic stem cell divisions correlates with cell fate.

Selected by ClaireS & SophieM

Background

Embryonic stem cells (ESCs) are the in vitro counterpart of cells of the early embryo, with the potential to form all cell types of the body. ESCs respond heterogeneously to extrinsic signals, posing a challenge for robust and efficient in vitro differentiation. Wolff et al. investigate the origins of cell-to-cell variability in human ESCs (hESCs) and how this affects cell fate.

 

What we like about this pre-print

While transcriptional reporters are the norm, here the authors opted for a protein fusion reporter, to directly observe OCT4 (a pluripotency-associated transcription factor) in hESCs. They used live imaging to painstakingly track and quantify OCT4 protein levels across multiple rounds of cell divisions. In 38% of cell divisions, OCT4-mCherry was unequally distributed to daughter cells, producing an OCT4-HI cell and a differentiation-prone OCT4-LO cell. These data complement studies in mouse ESCs correlating TF (e.g. Nanog, Dppa3, Hhex) expression levels with functional properties. Such studies, identifying underlying cell fate biases, might be harnessed to improve hESC differentiation efficiencies.

 

Although asymmetric protein segregation is commonplace in invertebrates, less is known about this phenomenon in mammalian systems. Conceivably other proteins are asymmetrically partitioned to daughter cells and cell fate may be influenced by the relative balance of inherited factors e.g. regulators of pluripotency, differentiation, cell cycle and metabolism. It is tempting to speculate that asymmetric TF inheritance may also bias cell fate in vivo.

 

Open Questions

What governs the asymmetric allocation of proteins? As OCT4 is a mitotic bookmarking factor, asymmetric protein allocation at cell division implies differential OCT4 binding to sister chromatids. Is this stochastic or a regulated process? How long are differences sustained, inherited, or buffered and by what mechanism?

 

Further reading

Hormoz, S., Singer, Z. S., Linton, J. M., Antebi, Y. E., Shraiman, B. I., & Elowitz, M. B. (2016). Inferring Cell-State Transition Dynamics from Lineage Trees and Endpoint Single-Cell Measurements. Cell Syst, 3(5), 419-433 e418. doi:10.1016/j.cels.2016.10.015

 

Pauklin, S., Madrigal, P., Bertero, A., & Vallier, L. (2016). Initiation of stem cell differentiation involves cell cycle-dependent regulation of developmental genes by Cyclin D. Genes Dev, 30(4), 421-433. doi:10.1101/gad.271452.115

 

Torres-Padilla, M. E., & Chambers, I. (2014). Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage. Development, 141(11), 2173-2181. doi:10.1242/dev.102624

 

White, M. D., Angiolini, J. F., Alvarez, Y. D., Kaur, G., Zhao, Z. W., Mocskos, E., . . . Plachta, N. (2016). Long-Lived Binding of Sox2 to DNA Predicts Cell Fate in the Four-Cell Mouse Embryo. Cell, 165(1), 75-87. doi:10.1016/j.cell.2016.02.032

 

 

Does protein allocation at cell division impact cell fate? Asymmetric inheritance of the pluripotency-associated factor OCT4 during human embryonic stem cell divisions correlates with cell fate.

 

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  • Author's response

    Jeremy Purvis shared

    Do you think that asymmetric protein allocation at cell division is stochastic or regulated?

    “This is an interesting question that remains to be answered. Previous work in mouse stem cells showed that localized Wnt signaling can favor the distribution of pluripotency factors to one of the daughter cells, so my tendency is to think that this partitioning process is, at least in part, subject to meaningful cellular regulation.”

     

    What is the biggest challenge in interpreting these data?

    “One challenge we continually face is how to classify the fate of an individual cell. It is convenient to think of cells as belonging into discrete classes, but in reality they often fall along a continuum in terms of expression levels of measureable factors. This is further complicated by the fact that a cell may very well be on its way to a particular fate, but we have analyzed it before it actually got there. The term “fate” implies some static, ultimate destination. Perhaps we should adopt the use of the phrase “cell journey”?”

     

    How do you think your findings could impact the field in general?

    “… this study has forced us to realize the cells that receive a differentiation stimulus are usually not the same cells making a measureable fate decision. Rather, cell fate decisions are usually not realized until 2 or 3 generations later by the offspring of the treated cells. I hope this work in particular underscores the importance of inheritance in influencing fate decisions.”

    Lineage of OCT4
    expression dynamics.

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