Defining the mechanisms that establish heterochromatin and promote silencing of tumour suppressor genes using electron microscopy Cancer Research UK Manchester Institute in United Kingdom

This PhD project at the Cancer Research UK Manchester Institute focuses on understanding the mechanisms that establish heterochromatin and promote silencing of tumour suppressor genes using advanced electron microscopy techniques. The genome is organised into heterochromatin (silent) and euchromatin (active) compartments, and disruptions in heterochromatin regulation are frequently observed in cancer. For example, amplifications in SETDB1, an enzyme responsible for depositing the repressive histone modification H3K9me2/3, are found in various cancers and can lead to aberrant silencing of tumour suppressor genes and endogenous retroviral elements, promoting tumorigenesis.

The Chromatin Regulation in Cancer Group, led by Dr Alice Sherrard, investigates how chromatin structure is regulated during mammalian development and cancer. The lab has developed innovative tools combining 3D electron microscopy (EM) with nanogold labelling to visualise chromatin ultrastructure in situ and link it to molecular regulators and functions. These approaches have revealed previously unrecognised structural properties of chromatin, distinguishing stages of cell differentiation and epigenetic remodelling. Structural subclasses of heterochromatin, their function, and molecular regulation—important in cancer—will be explored in this project.

The student will map distinct chromatin structural configurations to specific classes of heterochromatin marked by known epigenetic regulators using EM and nanogold labelling. Functional and temporal dynamics of heterochromatin assembly will be dissected by labelling ERV elements in a time-course following SETDB1 overexpression. Experiments will utilise copy number amplifications and loss-of-function mutations observed in cancer to define how chromatin structure regulates gene silencing. CRISPR will be used to deplete key heterochromatin regulators and define their roles in establishing silent chromatin compartments. Integrating genomic profiling and high-resolution EM will generate a comprehensive, multi-scale model of heterochromatin assembly and its dysregulation in oncogenesis.

The successful candidate will join a leading global cancer research institute and receive training in chromatin biology, light and electron microscopy, image analysis, genome editing, and genomics. Applicants should have a strong academic track record and experience in chromatin biology, microscopy, or cancer research. Motivation, creativity, and ambition are highly valued. Entry is in September 2026. The application deadline is April 6, 2026.

For further information and to apply, visit the project link. This opportunity is ideal for students interested in cancer biology, chromatin regulation, and advanced imaging techniques.