Dr Brian Hendrich
Transcriptional Control of Stem Cell Fate
Department of Biochemistry, University of Cambridge
Brian Hendrich grew up near Seattle, Washington, and is conseqeuntly a consummate coffee snob. He got his PhD from Stanford University in 1995 working on X chromosome inactivation with Huntington Willard. In 1995 he joined the lab of Adrian Bird at the University of Edinburgh and participated in the discovery and characterisation of a family of methyl-CpG binding proteins in mammals. In 2001 he started his own laboratory at the University of Edinburgh. In 2008 he moved to the Wellcome Trust Centre for Stem Cell Research in Cambridge.
He is currently a Wellcome Trust Senior Research Fellow in the Basic Biomedical Sciences, and Director of the PhD Programme in Stem Cell Biology and Medicine for the Cambridge Stem Cell Institute.
He can often be found cycling the quieter roads of East Anglia, in search of a hill.
Embryonic stem (ES) cells hold enormous promise for personalised medicine and drug discovery since they can be maintained indefinitely and are pluripotent; that is they have the potential to form any adult cell type. While pluripotency makes ES cells potentially very useful, it also presents a problem: how do you get them to make the cell type you want, and not one you don't? Differentiation of pluripotent cells is exquisitely organised during normal embryogenesis, but controlling differentiation of stem cells in culture presents a major challenge. Since all cells in an organism are genetically identical, the observable differences in their functions and behaviours come down to which genes they express and which genes they don’t express. Therefore in order to understand how to direct cellular identity, we seek to understand how cells regulate gene expression during differentiation. We also seek to understand how subtle differences in gene expression patterns in seemingly identical cells influence any subsequent differentiation decisions. To do this we focus on how the DNA is packaged in the cell and study the proteins involved in regulating this chromatin packaging. We use biochemistry, genetics, in vitro stem cell culture and manipulation, single cell analyses, genome-wide analyses and collaborate with bioinformaticians and computer programmers to better understand how control of transcription facilitates decision making in stem cells. By understanding how ES cells make different developmental decisions this work will bring the medical promise of stem cells closer to realisation.
Cells of early mammalian embryos have the potential to develop into any adult cell type, and are thus said to be pluripotent. Pluripotency is lost during embryogenesis as cells begin to commit to specific developmental pathways.
The goal of the group is to understand the transcriptional regulatory mechanisms that underpin the ability of a homogeneous population of pluripotent cells to give rise to the massive heterogeneity existing in somatic tissues. To achieve this they are using a combination of biochemistry, genetics, developmental biology, bioinformatics, ES cell manipulation, in vitro differentiation, proteomics, and gene expression analyses.
We are part of the EU FP7 Project "4DCellFate"
Follow us on Twitter: @BDH_Lab
Click on the button above to see a morula turn into a blastocyst!
(Video Credit Aoife O'Shaughnessy-Kirwan)
PHOTO CREDIT: Anzy Miller and her Troupe of ScienceArtists
Keisuke Kaji 2002-2007 Currently: ESF Research Fellow, University of Edinburgh
Patrick McDonel 2007-2011 Currently: Postdoctoral Researcher, The Whitehead Institute, MIT
Dziugas Gineitis 2007-2009 Currently: Research Scientist (Industry, UK)
Paulina Latos 2008-2011 Currently: Postdoctoral Researcher, The Babraham Institute
Erin Knock 2009-2012 Currently: Postdoctoral Researcher, University of Toronto
. Jason Signolet, Wellcome Trust/MRC Four Year PhD Student, University of Cambridge, PhD Awarded 2014. Currently: Data Analyist and Koala Impersonator, Adelaide
. Aoife O'Shaughnessy, BBSRC Case Studentship with Pfizer PLC, University of Cambridge, PhD Awarded 2012. Currently: Postgraduate Student, University of Cardiff AND Postdoctoral Scientist, Talisman Therapeutics Limited
. Ita Costello, Wellcome Trust Four Year PhD Student, University of Edinburgh, PhD Awarded 2008. Currently: Postdoctoral Research Fellow, University of Oxford
. Christine Powell (Heliwell), MRC PhD Studentship, University of Edinburgh, PhD Awarded 2007. Currently: Administrator, University of Edinburgh
. Isabel Martin Caballero, School of Biological Sciences PhD Studentship, University of Edinburgh, PhD Awarded 2006. Currently: Postdoctoral Fellow, Karolinska Instituet
. Lars Hansen, Masters Student from Raboud University Nijmegen, 2011-2012. Currently: PhD student, Oxford University
. Philip Brennecke, Erasmus visiting Masters Student from Freie Universität, Berlin. 2008-2009. Currently: Postdoctoral Fellow, Stanford University.
. Manoe Janssen, Erasmus visiting Masters Student from Raboud University Nijmegen, 2008. Currently: Postdoctoral Fellow K.U. Leuven, Belgium
Plain EnglishEmbryonic stem cells can either make more copies of themselves, or differentiate to form any cell type in the body. How cells make the decision to differentiate, and which cell type to differentiate into, is controlled by gene expression patterns. We are studying how precise control of gene expression allows cells to make these decisions.
O'Shaughnessy-Kirwan, A., Signolet, J., Costello, I., Gharbi, S., and Hendrich, B. (2015). Constraint of gene expression by the chromatin remodelling protein CHD4 facilitates lineage specification. Development, 142(15), 2586–2597. doi:10.1242/dev.125450
Knock, E., Pereira, J., Lombard, P.D., Dimond, A., Leaford, D., Livesey, F.J. and Hendrich, B. (2015) The methyl binding domain 3/nucleosome remodeling and deacetylase complex regulates neural cell fate determination and terminal differentiation in the cerebral cortex. Neural Development. 10:13 doi: 10.1186/s13064-015-0040-z
- Bertone, P., Hendrich, B., and Silva, JCR. (2015) Mbd3 and deterministic reprogramming. BioRXiv doi: http://dx.doi.org/10.1101/013904
- Signolet, J. and Hendrich, B. (2014) The function of chromatin modifiers in lineage commitment and cell fate specification. FEBS J. DOI: 10.1111/febs.13132
dos Santos, R., Tosti, L., Radzisheuskaya, A., Caballero, I.M., Kaji, K*., Hendrich, B*. and Silva, J.C.R. * (2014) Mbd3/NuRD facilitates induction of pluripotency in a context dependent manner Cell Stem Cell doi: 10.1016/j.stem.2014.04.019 *co-senior authors
O’Shaughnessy, A. and Hendrich, B. (2013) CHD4 in the DNA-damage response and cell-cycle progression: not so NuRDY now. Biochem. Soc. Trans. 41(3):777-782. doi:10.1042/BST20130027.
- Reynolds, N., O’Shaughnessy, A. and Hendrich, B. (2013) "Transcriptional repressors: multifaceted regulators of gene expression" Development, 140(3), 505–512. doi:10.1242/dev.083105
- Reynolds, N., Latos, P., Hynes-Allen, A., Loos, R., Leaford, D., O’Shaughnessy, A., Mosaku, O., Signolet, J., Brennecke, P., Kalkan, T., Costello, I., Humphreys, P., Mansfield, W., Nakagawa, K., Strouboulis, J., Behrens, A. Bertone, P., and Hendrich, B. (2012) “NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment” Cell Stem Cell 10(5): 583-594. 10.1016/j.stem.2012.02.020; Open Access: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402183/
Latos, P.A., Helliwell, C., Mosaku, O., Dudzinska, D.A., Stubbs, B.,Berdasco, M., Esteller, M., Hendrich, B. (2012) NuRD-dependent DNA methylation prevents ES cells from accessing a trophectoderm fate. Biology Open
McDonel, P., Demmers, J., Tan, D.M.W., Watt, F., and Hendrich, B. (2012) “Sin3a is essential for the genome integrity and viability of pluripotent cells.” Developmental Biology 363:62, doi:10.1016/j.ydbio.2011.12.019
- Reynolds, N., Salmon-Divon, M., Dvinge, H., Balasooriya, G., Leaford, D., Hynes-Allen, A., Behrens, A., Bertone, P. and Hendrich, B. (2012) “NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repression” EMBO Journal 31:593, doi:10.1038/emboj.2011.431