Menu

Close

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.

 

Posted on: 14th February 2018 , updated on: 20th February 2018

Read preprint (1 votes)




  • 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.

    Have your say

    Your email address will not be published. Required fields are marked *

    This site uses Akismet to reduce spam. Learn how your comment data is processed.

    Sign up to customise the site to your preferences and to receive alerts

    Register here

    Also in the cell biology category:

    Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions

    Ruensern Tan, Aileen J. Lam, Tracy Tan, et al.

    AND

    Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes

    Valerie Siahaan, Jochen Krattenmacher, Amayra Hernandez-Vega, et al.



    Selected by Satish Bodakuntla

    The modular mechanism of chromocenter formation in Drosophila

    Madhav Jagannathan, Ryan Cummings, Yukiko M Yamashita



    Selected by Maiko Kitaoka

    1

    The cell wall regulates dynamics and size of plasma-membrane nanodomains in Arabidopsis.

    Joseph Franics McKenna, Daniel Rolfe, Stephen E D Webb, et al.



    Selected by Marc Somssich

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals

    Salah Mahmoudi, Elena Mancini, Alessandra Moore, et al.



    Selected by Shikha Nayar

    DNA microscopy: Optics-free spatio-genetic imaging by a stand-alone chemical reaction

    Joshua A. Weinstein, Aviv Regev, Feng Zhang



    Selected by Theo Sanderson

    2

    The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

    Federico Germani, Daniel Hain, Denise Sternlicht, et al.



    Selected by Rohan Khadilkar

    Drosophila kinesin-8 stabilises kinetochore-microtubule interaction

    Tomoya Edzuka, Gohta Goshima



    Selected by Ben Craske, Thibault Legal and Toni McHugh

    1

    Unjamming overcomes kinetic and proliferation arrest in terminally differentiated cells and promotes collective motility of carcinoma.

    Andrea Palamidessi, Chiara Malinverno, Emanuela FRITTOLI, et al.



    Selected by Tim Fessenden

    1

    Tension on kinetochore substrates is insufficient to prevent Aurora-triggered detachment

    Anna K de Regt, Charles L Asbury, Sue Biggins



    Selected by Angika Basant

    1

    Single-cell RNA sequencing reveals novel cell differentiation dynamics during human airway epithelium regeneration

    Sandra Ruiz Garcia, Marie Deprez, Kevin Lebrigand, et al.



    Selected by Rob Hynds

    1

    Actomyosin-driven tension at compartmental boundaries orients cell division independently of cell geometry in vivo

    Elena Scarpa, Cedric Finet, Guy Blanchard, et al.



    Selected by Ivana Viktorinová

    Molecular organization of integrin-based adhesion complexes in mouse Embryonic Stem Cells

    Shumin Xia, Evelyn K.F. Yim, Pakorn Kanchanawong

    AND

    Superresolution architecture of pluripotency guarding adhesions

    Aki Stubb, Camilo Guzmán, Elisa Närvä, et al.



    Selected by Nicola Stevenson, Amanda Haage

    Transcriptional initiation and mechanically driven self-propagation of a tissue contractile wave during axis elongation

    Anais Bailles, Claudio Collinet, Jean-Marc Philippe, et al.



    Selected by Sundar Naganathan

    1

    Bridging the divide: bacteria synthesizing archaeal membrane lipids

    Laura Villanueva, F. A. Bastiaan von Meijenfeldt, Alexander B. Westbye, et al.

    AND

    Extensive transfer of membrane lipid biosynthetic genes between Archaea and Bacteria

    Gareth A. Coleman, Richard D. Pancost, Tom A. Williams



    Selected by Gautam Dey

    1

    Revealing the nanoscale morphology of the primary cilium using super-resolution fluorescence microscopy

    Joshua Yoon, Colin J. Comerci, Lucien E. Weiss, et al.



    Selected by Gautam Dey

    Also in the developmental biology category:

    The cell wall regulates dynamics and size of plasma-membrane nanodomains in Arabidopsis.

    Joseph Franics McKenna, Daniel Rolfe, Stephen E D Webb, et al.



    Selected by Marc Somssich

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    A Scube2-Shh feedback loop links morphogen release to morphogen signaling to enable scale invariant patterning of the ventral neural tube

    Zach Collins, Kana Ishimatsu, Tony Tsai, et al.



    Selected by Teresa Rayon

    1

    Epiblast formation by Tead-Yap-dependent expression of pluripotency factors and competitive elimination of unspecified cells

    Masakazu Hashimoto, Hiroshi Sasaki



    Selected by Sarah Bowling, Teresa Rayon

    Single cell transcriptomics reveals spatial and temporal dynamics of gene expression in the developing mouse spinal cord

    Julien Delile, Teresa Rayon, Manuela Melchionda, et al.



    Selected by Reena Lasrado

    1

    The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner

    Federico Germani, Daniel Hain, Denise Sternlicht, et al.



    Selected by Rohan Khadilkar

    Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila

    Charles A Seller, Chun-Yi Cho, Patrick H O'Farrell



    Selected by Gabriel Aughey

    A histidine kinase gene is required for large radius root tip circumnutation and surface exploration in rice

    Kevin R Lehner, Isaiah Taylor, Erin N McCaskey, et al.



    Selected by Martin Balcerowicz

    Actomyosin-driven tension at compartmental boundaries orients cell division independently of cell geometry in vivo

    Elena Scarpa, Cedric Finet, Guy Blanchard, et al.



    Selected by Ivana Viktorinová

    Molecular organization of integrin-based adhesion complexes in mouse Embryonic Stem Cells

    Shumin Xia, Evelyn K.F. Yim, Pakorn Kanchanawong

    AND

    Superresolution architecture of pluripotency guarding adhesions

    Aki Stubb, Camilo Guzmán, Elisa Närvä, et al.



    Selected by Nicola Stevenson, Amanda Haage

    Transcriptional initiation and mechanically driven self-propagation of a tissue contractile wave during axis elongation

    Anais Bailles, Claudio Collinet, Jean-Marc Philippe, et al.



    Selected by Sundar Naganathan

    1

    Signaling dynamics control cell fate in the early Drosophila embryo

    Heath E Johnson, Stanislav Y Shvartsman, Jared E Toettcher



    Selected by Yara E. Sánchez Corrales

    1

    Three-dimensional tissue stiffness mapping in the mouse embryo supports durotaxis during early limb bud morphogenesis

    Min Zhu, Hirotaka Tao, Mohammad Samani, et al.



    Selected by Natalie Dye

    PUMILIO hyperactivity drives premature aging of Norad-deficient mice

    Florian Kopp, Mehmet Yalvac, Beibei Chen, et al.



    Selected by Carmen Adriaens

    Synergy with TGFβ ligands switches WNT pathway dynamics from transient to sustained during human pluripotent cell differentiation

    Joseph Massey, Yida Liu, Omar Alvarenga, et al.



    Selected by Pierre Osteil

    1

    3D Tissue elongation via ECM stiffness-cued junctional remodeling

    Dong-Yuan Chen, Justin Crest, Sebastian J Streichan, et al.



    Selected by Sundar Naganathan

    Also in the molecular biology category:

    The modular mechanism of chromocenter formation in Drosophila

    Madhav Jagannathan, Ryan Cummings, Yukiko M Yamashita



    Selected by Maiko Kitaoka

    1

    The structural basis for release factor activation during translation termination revealed by time-resolved cryogenic electron microscopy

    Ziao Fu, Gabriele Indrisiunaite, Sandip Kaledhonkar, et al.



    Selected by David Wright

    The cell wall regulates dynamics and size of plasma-membrane nanodomains in Arabidopsis.

    Joseph Franics McKenna, Daniel Rolfe, Stephen E D Webb, et al.



    Selected by Marc Somssich

    Psychiatric risk gene NT5C2 regulates protein translation in human neural progenitor cells

    Rodrigo R.R. Duarte, Nathaniel D. Bachtel, Marie-Caroline Cotel, et al.



    Selected by Joanna Cross

    DNA microscopy: Optics-free spatio-genetic imaging by a stand-alone chemical reaction

    Joshua A. Weinstein, Aviv Regev, Feng Zhang



    Selected by Theo Sanderson

    2

    Rapid embryonic cell cycles defer the establishment of heterochromatin by Eggless/SetDB1 in Drosophila

    Charles A Seller, Chun-Yi Cho, Patrick H O'Farrell



    Selected by Gabriel Aughey

    Signaling dynamics control cell fate in the early Drosophila embryo

    Heath E Johnson, Stanislav Y Shvartsman, Jared E Toettcher



    Selected by Yara E. Sánchez Corrales

    1

    PUMILIO hyperactivity drives premature aging of Norad-deficient mice

    Florian Kopp, Mehmet Yalvac, Beibei Chen, et al.



    Selected by Carmen Adriaens

    Target-specific precision of CRISPR-mediated genome editing

    Anob M Chakrabarti, Tristan Henser-Brownhill, Josep Monserrat, et al.



    Selected by Rob Hynds

    1

    Transient intracellular acidification regulates the core transcriptional heat shock response

    Catherine G Triandafillou, Christopher D Katanski, Aaron R Dinner, et al.



    Selected by Srivats Venkataramanan

    1

    Memory sequencing reveals heritable single cell gene expression programs associated with distinct cellular behaviors

    Sydney M Shaffer, Benjamin L Emert, Ann E. Sizemore, et al.



    Selected by Leighton Daigh

    2

    Site-specific K63 ubiquitinomics reveals post-initiation regulation of ribosomes under oxidative stress

    Songhee Back, Christine Vogel, Gustavo M Silva



    Selected by Srivats Venkataramanan

    1

    Quantitative, real-time, single cell analysis in tissue reveals expression dynamics of neurogenesis

    Cerys S Manning, Veronica Biga, James Boyd, et al.



    Selected by Teresa Rayon

    The cis-regulatory logic underlying abdominal Hox-mediated repression versus activation of regulatory elements in Drosophila

    Arya Zandvakili, Juli Uhl, Ian Campbell, et al.



    Selected by Clarice Hong

    1

    Moving beyond P values: Everyday data analysis with estimation plots

    Joses Ho, Tayfun Tumkaya, Sameer Aryal, et al.



    Selected by Gautam Dey

    1

    A limited number of double-strand DNA breaks are sufficient to delay cell cycle progression.

    Jeroen van den Berg, Anna G. Manjon, Karoline Kielbassa, et al.



    Selected by Leighton Daigh
    Close