Many mammalian tissues and organs gradually lose their regenerative capacities after development, leading to degenerative diseases in later life. In adult organs, various cell types perform their essential functions with only limited cell replacement for tissue maintenance and healing. In the cell nucleus, epigenetic marks on the histones and DNA help to set up active and repressive chromatin states, which are thought to maintain gene activity patterns in cell lineages but also regulate overall nuclear and chromosome function. Using advanced microscopy, immunodetection of nuclear proteins and chromatin immunoprecipitation (ChIP), we have identified specific epigenetic signatures of mouse cardiac development. We hypothesise that the reorganisation of chromatin in these cells contributes to the post-mitotic non regenerative state of the adult heart. We will explore this using a variety of experimental and computational approaches.
The project aims to:
(i) determine changes in protein composition, epigenetic marks and nuclear localisation of condensed chromatin during mouse embryonic heart development. Experiments comparing embryonic heart tissue and in vitro cultured cardiomyocytes will then be used to test whether alterations in epigenetic markers and chromatin composition can affect their spatial associations in the nucleus and mitotic activity.
(ii) discover how chromosomes and chromatin are reorganised from murine cardiac progenitors to differentiated heart cells by generating novel chromatin conformation capture (CCC) data followed by bioinformatics analysis.
(iii) integrate these CCC analyses with unpublished complementary gene expression data and ChIP epigenomic mapping data for these tissues, as well as publicly available genome-wide data sets (e.g. Gilsbach et al, 2014), to assess the functional impacts of altered nuclear organisation.
(iv) exploit the large volumes of publicly available chromatin genomic data for human adult and fetal heart tissue samples (Roadmap Epigenomics Consortium, 2015) to examine the consistency of such impacts between mouse and human cells.
This PhD project will involve two collaborating research groups, combining expertise in nuclear organisation dynamics with advanced bioinformatics, to reveal the epigenetic signalling mechanisms and pathways contributing to the post-mitotic state of cardiac cells. The research outcomes will provide more knowledge on the role of epigenetics in heart development and maturation, which could lead to better preservation of regenerative capacity in the adult heart.
The PhD study will provide knowledge and transferrable skills in epigenetics, developmental biology, molecular biology and bioinformatics through genomic analysis of chromatin and gene expression, immunofluorescence confocal microscopy and image analysis. The studentship includes a 3-month placement in industry with a mentor involved in the project.
1. Gilsbach et al., 2014. Dynamic DNA methylation orchestrates cardiomyocyte development, maturation and disease. Nat Commun 5: 5288.
2. Roadmap Epigenomics Consortium. 2015. Integrative analysis of 111 reference human epigenomes. Nature 518: 317-30.