Hendrich Group Transcriptional control of stem cell fate Since all cells in an organism are genetically identical, the observable differences in their functions and behaviours come down to which genes they turn on and which genes they turn off. We seek to understand how stem cells execute the changes in gene expression needed to successfully and appropriately respond to differentiation signals. Our main focus has been the Nucleosome Remodelling and Deacetylation Complex, or NuRD, and its chromatin remodelling subunit CHD4. NuRD is an abundant chromatin remodeller conserved throughout metazoans. We’ve shown NuRD both reduces transcriptional noise and facilitates signal-responsive transcriptional activation to facilitate developmental decisions. Schematic of NuRD function at Enhancer sequences. NuRD (pink) acts on enhancers to regulate the binding of transcription factors (different coloured ovals) and the positioning of nucleosomes (orange circles). This allows the enhancer to respond properly when a signal is received. Other chromatin remodellers (green) perform distinct, occasionally opposing functions at these enhancers. Together they ensure the enhancer is in the correct chromatin configuration to be able to appropriately respond to extracellular signals and instruct a new gene expression programme appropriate for the instructed cell fate. We are currently studying how chromatin remodelling proteins control the 2D and 3D genome to orchestrate how a cell responds to inductive signals. We look at how the interplay between chromatin accessibility, transcription factor binding, 3D genome architecture and transcription is influenced by ATPase-dependent chromatin remodellers over time. Using human and mouse pluripotent stem cells, we define how cell fate decisions are made, with the ultimate goal of learning how we might control cellular responses. We apply this knowledge to understand why mutations in genes encoding chromatin remodelling proteins cause human developmental disorders, and can predispose cells towards forming cancers. This mouse ES cell nucleus has been stained with a DNA dye (left), assayed for accessible chromatin (ATAC-See, middle) prior to 3D genome structure calculation (right). This allows us to understand how changes in genome accessibility, and eventually changes in protein localisation, correspond to changes in 3D genome structure. Recent Publications Bornelöv, S., Reynolds N., et al. (2018) The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression. https://doi.org/10.1016/j.molcel.2018.06.003Lando, D., et al. (2024) Enhancer-promoter interactions are reconfigured through the formation of long-range multiway hubs as mouse ES cells exit pluripotency. https://doi.org/doi:10.1016/j.molcel.2024.02.015Montibus, B., Ragheb, R., (2024) The Nucleosome Remodelling and Deacetylation complex coordinates the transcriptional response to lineage commitment in pluripotent cells. https://doi.org/10.1242/bio.060101 Basu, S., Shukron, O.,et al. (2023) Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD. https://doi.org/10.1038/s41594-023-01095-4 Ragheb, R., et al. (2020). Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex. https://doi.org/10.1016/j.scr.2020.101867 Contact: B.D.Hendrich@exeter.ac.uk @surfinnurd.bsky.social