Inheritance of OCT4 predetermines fate choice in human embryonic stem cells
Posted on: 14 February 2018 , updated on: 20 February 2018
Preprint posted on 26 January 2018
Article now published in Molecular Systems Biology at http://dx.doi.org/10.15252/msb.20178140
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 Claire Simon & Sophie MorganiCategories: cell biology, developmental biology, molecular biology
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
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