Reprogramming the epigenome for stem cells and in ageing

Lead Research Organisation: University of Cambridge
Department Name: Cancer Research UK Cambridge Institute

Abstract

Theme: World-Class Underpinning Bioscience

Epigenetic information in the genome is important for normal development and its deregulation can be associated with various diseases. Epigenetic information is generally stable in differentiated cells in the adult organism, though it degrades during ageing. However in germ cells, early embryos, naïve embryonic stem cells and iPS cells genome-wide reprogramming of epigenetic information takes place. Epigenetic reprogramming is associated with the return of the genome to pluripotency or potentially totipotency, the erasure of epimutations, resetting parental imprints, and possibly the repression of retrotransposons in the germline. Epigenetic reprogramming is also critical for experimental reprogramming such as cloning by nuclear transfer, cell fusion, and iPS cell generation. Erasure of epigenetic information in the germ line is incomplete however and this may result in transgenerational epigenetic inheritance. Single cell DNA methylation sequencing has also revealed substantial epigenetic heterogeneity between cells, which may be associated with transcriptional and functional diversification of cells during development or ageing. Predictable epigenetic changes occur during the ageing process raising the question of whether there is an epigenetic programme that might underlie aspects of ageing and functional decline.

You will be working in an internationally leading lab that studies the mechanisms and functional consequences of epigenetic reprogramming. You will study the molecular pathways of reprogramming especially of demethylation of DNA which includes passive and active demethylation. Passive demethylation can occur by regulation of Dnmt1 and Uhrf1 including by cell signaling principles. Active demethylation occurs by oxidation of methylcytosine (5mC) to hydroxymethylcytosine (5hmC), formylcytosine (5fC), and carboxylcytosine (5caC) by the TET enzymes or by deamination by AID/APOBEC enzymes and base excision repair. You will be using mouse knockout and cell models, or biochemical approaches, to study these pathways. Our approaches include epigenomics, bioinformatics, cell signalling, and modelling which you will have the opportunity to engage with, including single cell epigenomics through the affiliated Single Cell Genomics Centre (http://www.sanger.ac.uk/research/projects/singlecellcentre, at the nearby Sanger Institute). The functional consequences of manipulating reprogramming pathways for normal development, ageing, pluripotency and iPS cell generation will also be investigated. You will be joining an enthusiastic and collaborative team of students and postdocs embedded in one of the largest programmes of Epigenetics and Nuclear Dynamics science within Europe.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011194/1 01/10/2015 30/09/2023
1804447 Studentship BB/M011194/1 01/10/2016 31/03/2021 Diljeet Gill
 
Description We have been able to rejuvenate human cells by about 40 years using transient stem cell reprogramming (the process where body cells are converted into embryonic-like stem cells).
Exploitation Route This finding could lead to the development of novel anti-ageing therapies.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Involved in LifeLab in Peterborough 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I was involved in LifeLab 2018 in Peterborough to present the Race against the ageing clock exhibit. I was engaging with the general public and demonstrating the activities we had on the stand.
Year(s) Of Engagement Activity 2018
 
Description Involved in the development of a stand at the Royal Society Summer Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was a part of the development team for our institute's stand at the Royal Society Summer Exhibition in 2018. I helped design an activity centred around my project, which demonstrated the process of iPSC reprogramming and how it influences the epigenetic clock. I also helped at the stand during the exhibition.
Year(s) Of Engagement Activity 2018
URL https://www.babraham.ac.uk/about-us/impact/public/special-projects/race-against-the-ageing-clock