Project Reference: TRG27-GEN-CE1

Project title: Decoding stochastic silencing of mammalian transposons using epigenome editing

Project outline

Tissue-specific gene regulation is essential for normal development and lifelong health. Transposable elements, which constitute 40-50% of human and mouse genomes, are typically silenced by epigenetic mechanisms to restrict their expression and transposition. However, incomplete or stochastic silencing can restore their regulatory potential, influencing nearby gene expression.

Epigenetic silencing is reset across the genome in early embryonic development as DNA methylation is erased and re-established. At newer transposable elements, re-establishment of silencing can vary between genetically-identical individuals, generating epigenetically variable elements (epialleles) that are maintained into adulthood. Variation likely reflects stochastic competition for DNA binding between transcription factors and epigenome modifiers. We will manipulate DNA binding sites and epigenetic marks during this crucial re-establishment period to define the order of events in epigenetic silencing.

This project will investigate the role of the methylation-sensitive transcription factor CTCF in the establishment and maintenance of epialleles. CTCF binding sites in epialleles will be removed by genome editing in vitro and in vivo, and inheritance of stochastic silencing will be tracked through mouse development. Targeted epigenome editing in the Agouti viable yellow mouse model will test the contribution of histone modifications to the inheritance of epigenetic states, in collaboration with international partners.

The findings from this project will provide mechanistic insights into the establishment of active and repressive epigenetic states. Tackling these underexplored regions of the genome will uncover how certain transposable elements escape silencing and influence gene regulation, informing transgene design in synthetic biology applications and interpretation of novel transposable element insertions in clinical genetics. 

Principal Supervisor

Dr Carol Edwards

Email address: cae28@cam.ac.uk

Department / Partner Institute: Genetics

Website: https://www.gen.cam.ac.uk/people/carol-edwards

BBSRC strategic theme

Understanding the rules of life