Brickman Group - Transcriptional Basis for Cell Fate Choice

Extrinsic Signals that Regulate Lineage Priming in ES cells

We have found that ES cells are composed of two populations of self-renewing and dynamically interconverting populations of early epiblast and primitive endoderm progenitors. We are interested in the signals that drive cells from one state to another and, signals that block cells, from a primed endoderm state, from entering differentiation. We are involved with a number of collaborative projects directed at collecting quantitative real time data to understand these processes.

Intrinsic Factors Regulating Heterogeneity and Self Renewal in ES cells

We have observed that the expression of a large number of early endoderm and epiblast genes change as ES cells transit between an early epiblast and endoderm state. We are interested in the transcriptional mechanisms that regulate this reversible lineage priming.

Function of the Conserved Transcription Factor Network Downstream of Oct4

We have identified a set of targets regulated by Oct4 and its homologues in Xenopus. We are interested in the means by which these factors regulate differentiation.

Transcriptional Basis for Lineage Specification in Endoderm

We have been using a number of genomewide technologies to characterise the changes transcription factor and RNA polymerase binding associated with specific precursor populations during the progressive specification of endoderm from pluripotent ES cells. We are particularly interested in the means by which signalling pathways impact on the progressive specification of transcription factor networks.

Polarity, Self Renewal and Differentiation

We have found that one of the major effectors of Fgf signalling during ES cell differentiation towards endoderm is remodelling of the extra-cellular matrix. This matrix is able to pattern naïve endoderm at the same time as inducing polarised endodermal epithelia. We are interested in the means by adhesive information is input into transcriptional programs. We have also associated the regulation of cellular adhesion with the Oct4 target network and are interested in how changes in cellular adhesion impact on cellular potency and commitment.

Previous Achievements

Revised Definitions of Pluripotency based on Low Level Dynamic Changes in Transcriptional States Associated with Cell Fate Choice in ES cells. We have developed a series of highly sensitive fluorescent reporter ES cell lines that have enabled us to define functionally distinct populations of self-renewing ES cells (Canham link, recent Current Opinions paper). These reporters employ a reiterated IRES sequence that functions as a translational amplifier to drive the expression of highly sensitive fluorescent proteins cells (see both Tsakiridis et al, NAR 2009 and Canham et al, PLoS Biol 2010) to give a highly sensitive and dynamic read out of lineage primed states in single cells.

A Model for Endoderm Induction and Expansion

We have established a number of additional fluorescent reporter ES cell lines alongside defined in vitro systems for embryonic differentiation. We have been able to derive, purify and expand defined anterior endoderm using these reporters. We were able to successfully expand ES cell derived endoderm for multiple passages and use our in vitro model system to uncover a new role for Fgf signalling during endoderm specification. (Morrison et al, Cell Stem Cell 2008, Livigni et al Curr Protocols In Stem Cell Biol, 2009).

A Defined and Conserved Oct4 Target Network

We have shown that the activity of Oct4, an essential ES cell transcription factor, is conserved in evolution and related to the activation of a conserved program of gene expression that suppresses differentiation and commitment in early development (Morrison and Brickman, Dev 2006, Hammachi et al, Cell Reporter 2012).

Research Profile

Josh Brickman has a background in molecular biology and gene regulation. From a PhD in transcription he trained in developmental biology as a post-doctoral fellow, working in early mouse, and Xenopus, as well as cultivating embryonic stem cells as a model for developmental biology. He began his own lab with research projects bridging early development in multiple models systems with ES cells in a hybrid approach aimed at understanding conserved mechanisms of pluripotency and self renewal.

He currently seeks to understand how transcription factors regulate cell fate choice in ES cells and early embryos. More specifically, Professor Brickman’s and his group investigate the basis for transcriptional priming and commitment in ES cells and early in the specification of the endoderm lineage. They hope to understand the relevance of these priming events to stem and progenitor cell potency.

Awards and Honours

Josh Brickamn is the recipient of several personal awards and numerous grants including, a Human Frontiers Science Program (HFSP) Long Term Fellowship. Wellcome Trust Research Career Development Fellowship and MRC Senior Non Clinical Fellowship. He is also coordinator of an HFSP program grant and serves on several advisory and editorial boards.

Key Recent Discoveries

Hamilton, W.B., Mosesson, Y., Monteiro, R.S., Emdal, K.B., Knudsen, T.E., Francavilla, C., Barkai, N., Olsen, J.V. and Brickman, J.M. (2019). Dynamic lineage priming is driven via direct enhancer regulation by ERK. Nature, doi: 10.1038/s41586-019-1732-z.

Weinert, B.T., Narita, T., Satpathy, S., Srinivasan, B., Hansen, B.K., Scholz, C., Hamilton, W.B., Zucconi, B.E., Wang, W.W., Liu, W.R., Brickman, J.M., Kesicki, E.A., Lai, A., Bromberg, K.D., Cole, P.A., and Choudhary, C. (2018). Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome. Cell 174, 231-244.e212, doi:10.1016/j.cell.2018.04.033.

Anderson, K.G.V., Hamilton, W.B., Roske, F.V., Azad, A., Knudsen, T.E., Canham, M.A., Forrester, L.M., and Brickman, J.M. (2017). Insulin fine-tunes self-renewal pathways governing naive pluripotency and extra-embryonic endoderm. Nature Cell Biology 19, 1164-1177, doi:10.1038/ncb3617.

Nissen, S.B., Perera, M., Gonzalez, J.M., Morgani, S.M., Jensen, M.H., Sneppen, K., Brickman, J.M.*, and Trusina, A.* (2017). Four simple rules that are sufficient to generate the mammalian blastocyst. PLoS Biol 15, e2000737, doi:10.1371/journal.pbio.2000737.  *joint senior author

Migueles, R.P., Shaw, L., Rodrigues, N.P., May, G., Henseleit, K., Anderson, K.G., Goker, H., Jones, C.M., de Bruijn, M.F., Brickman, J.M., and Enver, T. (2017). Transcriptional regulation of Hhex in hematopoiesis and hematopoietic stem cell ontogeny. Developmental Biology 424, 236-245, doi:10.1016/j.ydbio.2016.12.021.

Illingworth, R.S., Hölzenspies, J.J., Roske, F.V., Bickmore, W.A., and Brickman, J.M. (2016). Polycomb enables primitive endoderm lineage priming in embryonic stem cells. Elife 5, doi:10.7554/eLife.14926.

Martin Gonzalez, J., Morgani, S.M., Bone, R.A., Bonderup, K., Abelchian, S., Brakebusch, C., and Brickman, J.M. (2016). Embryonic Stem Cell Culture Conditions Support Distinct States Associated with Different Developmental Stages and Potency. Stem Cell Reports 7, 177-191, doi:10.1016/j.stemcr.2016.07.009.

Josh Brickman: Transcribing Patterns from the Library of Life