Prof M Merkenschlager, Prof Boris Lenhard
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
3D genome organisation, enhancer activity and gene transcription are of fundamental biological interest for understanding how the genome functions. They are also essential for normal development, and often disrupted in cancer. This project will explore how 3D genome organisation, enhancer activity and gene transcription are reconfigured during cell lineage choice and differentiation. We have generated Hi-C, ChIP-seq and RNA-seq data that capture defined stages of T cell lineage choice and differentiation. Analysis of these data will generate a compendium of enhancers and chromatin contacts that underlie gene expression changes in development. T cell differentiation is triggered by activation signals, which drive a transient wave of activation-related enhancer activity and gene expression. These transient, activation-driven changes are supplanted by the formation of stable, lineage-specific enhancers and gene expression patterns. Single cell RNA-seq will define the temporal relationship between this activation signature and the acquisition of lineage-specific enhancers and gene expression.
The project will also explore the role of architectural chromatin proteins cohesin and CTCF (Merkenschlager and Nora, 2015; Nora et al., 2017; Rao et al., 2017), and of extreme non-coding conservation (Harmston et al., 2017) in genome folding, enhancer activity and gene regulation. Cohesin and CTCF drive the folding of interphase chromosomes into self-interacting topologically associating domains (TADs) and more fine-grained contact domains (Merkenschlager and Nora, 2015; Nora et al., 2017; Rao et al., 2017). The largest and strongest TADs are characterised by non-coding elements with extreme sequence conservation (Harmston et al., 2017). These conserved non-coding elements (CNEs) function as enhancers, but their conservation is far greater than that of other enhancers, and remains unexplained by enhancer function or other known selective forces. We will ask how CNE interactions change when TAD formation is disrupted by depletion of CTCF and cohesin, and how this affects the regulation of CNE target genes. The results we will uncover new principles of genome organisation and transcriptional regulation.
The project is largely computational but also offers opportunities for wet lab work.
Candidates should ideally be ready to start their PhD in October 2018.
Funding Notes
This project is competition funded for students worldwide.
If successful the student would receive full tuition fee payment for 3.5 years as well as a tax free stipend amounting to £21,000pa paid in monthly instalments for the duration of their studentship.
References
Fudenberg G, Imakaev M, Lu C, Goloborodko A, Abdennur N, Mirny LA. 2016. Formation of Chromosomal Domains by Loop Extrusion. Cell Rep 15: 2038–2049.
Harmston N, Ing-Simmons E, Tan G, Perry M, Merkenschlager M, Lenhard B. 2017. Topologically associated domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation. Nat Commun, in press.
Merkenschlager M, Nora EP. 2015. CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation. Annu Rev Genomics Hum Genet 17: annurev–genom–083115–022339.
Nora EP, Goloborodko A, Valton A-L, Gibcus JH, Uebersohn A, Abdennur N, Dekker J, Mirny LA, Bruneau BG. 2017. Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization. Cell 169: 930–944.e22.
Rao S, Huang S-C, Hilaire BGS, Engreitz JM, Perez EM, et al. 2017. Cohesin Loss Eliminates All Loop Domains, Leading To Links Among Superenhancers And Downregulation Of Nearby Genes. bioRxiv.
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