Brian Hendrich

Brian Hendrich

Transcriptional control of stem cell fate.

Embryonic stem (ES) cells hold enormous promise for personalised medicine and drug discovery since they can be maintained indefinitely and are pluripotent. While pluripotency makes ES cells potentially very useful, it also presents a problem: how do you get them to make the cell type that you want, and not the ones that you don't? Differentiation of pluripotent cells is exquisitely organised during normal embryogenesis, but is very hard to control in culture. 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 repress. In order to understand how to direct cellular identity, we seek to understand how subtle differences in gene expression patterns in seemingly identical cells, resulting from changes in how regulatory sequences are packaged in chromatin, influence subsequent differentiation decisions. By understanding how pluripotent cells make different developmental decisions this work will bring the medical promise of stem cells closer to realisation.

Research objectives

  • How do signalling pathways and the chromatin remodelling machinery work together to control cell fate decisions?

  • How, mechanistically, does control of transcription factor access to regulatory sequences by chromatin remodelling proteins impact transcription?

  • What is the relationship between nuclear architecture, chromatin remodelling and transcription, and how do alterations in this relationship give rise to human disease?

Key publications

Burgold T, Barber M, Kloet S, Cramard J, Gharbi S, Floyd R, Kinoshita M, Ralser M, Vermeulen M, Reynolds N, Dietmann S, Hendrich B (2019). The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment. EMBO J., 38(12):e100788. doi: 10.15252/embj.2018100788

Bornelöv S, Reynolds N, Xenophontos M, Gharbi S, Johnstone E, Floyd R, Ralser M, Signolet J, Loos R, Dietmann S, Bertone P, Hendrich B (2018). The Nucleosome Remodeling and Deacetylation complex modulates chromatin structure at sites of active transcription to fine-tune gene expression. Mol. Cell, 71(1):56-72. doi: 10.1016/j.molcel.2018.06.003

Stevens TJ, Lando D, Basu S, Atkinson LP, Cao Y, Lee SF, Leeb M, Wohlfahrt KJ, Boucher W, O'Shaughnessy-Kirwan A, Cramard J, Faure AJ, Ralser M, Blanco E, Morey L, Sansó M, Palayret MGS, Lehner B, Di Croce L, Wutz A, Hendrich B, Klenerman D, Laue ED (2017). 3D structures of individual mammalian genomes studied by single-cell Hi-C. Nature, 544(7648):59-64. doi: 10.1038/nature21429

Miller A, Ralser M, Kloet SL, Loos R, Nishinakamura R, Bertone P, Vermeulen M, Hendrich B (2016). Sall4 controls differentiation of pluripotent cells independently of the Nucleosome Remodelling and Deacetylation (NuRD) complex. Development, 143(17):3074-3084. doi: 10.1242/dev.139113

O'Shaughnessy-Kirwan A, Signolet J, Costello I, Gharbi S, 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