Investigating regulatory mechanisms of cardiac development, repair and regeneration.
A heart attack occurs when blood flow to a large portion of the heart decreases or stops, causing damage to the heart muscle. Nearly one billion of muscle cells are permanently lost after such event and replaced by non-contractile scar tissue in a process called fibrosis that further compromises the function of the heart and ultimately, leads to heart failure. To date, no treatment has been effective in mending the heart following a heart attack. Our recent work has shown that the heart attempts to replenish its damaged tissue, by reverting to similar processes that were used in the embryo to build the heart before birth. In particular, cells from the outer layer of the heart, the epicardium, become activated and undergo a process called epithelial-to-mesenchymal transition (EMT), but this activation is transient and insufficient to support new blood vessel and muscle growth as it happens in the embryo.
Cell fate decisions underlying EMT are directed by sequence-specific DNA binding factors, such as the transcription factor (TF) Wilms’ tumour 1 (WT1). Whilst a requirement for WT1 in mammalian heart development has been ascribed following characterisation of loss-of-function models, the upstream regulatory mechanisms underpinning its activation, as well as WT1 downstream transcriptional targets remain elusive. With regards to the former, we have identified a role for chromatin-remodelling (Vieira et al. Nature Communications, 2017) and are interrogating further epigenetic mechanisms, namely regulation by antisense long noncoding RNAs and noncoding regulatory sequences (enhancers). Likewise, unbiased screens integrating single cell RNA-sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) are being developed in the lab to identify further regulators of epicardial EMT. With regards to the transcriptional targets of WT1, Cleavage Under Targets and Release Using Nuclease (CUT&RUN) is being used to identify WT1-binding sites in the developing heart. Elucidating the transcriptional network downstream of WT1 will improve our understanding of the essential role of this TF in epicardial formation and EMT.
In addition, my lab retains an interest in understanding cell-cell interactions taking place at the epicardium-myocardium interface that support the development of the coronary vasculature and cardiac lymphatic network (Klotz*, Norman*, Vieira* et al. Nature, 2015), as well as patterning of the cardiac autonomic system. A better understanding of the cellular and molecular mechanisms supporting mammalian heart development is poised to identify molecular targets to effect (adult) heart repair and regeneration.
British Heart Foundation (Intermediate Basic Science Research Fellowship)
British Heart Foundation Oxford Centre of Research Excellence (Pump Priming Grant)
10 May 2022
Pint of Science is the world’s largest public science festival bringing researchers to local pubs, cafes and spaces to share their scientific discoveries with the public.
14 February 2022
Two projects aimed at tackling heart failure led by Associate Professor Sarah De Val and Dr Joaquim Vieira are to be funded by the 2022 TCS London Marathon with the British Heart Foundation as its Charity of the Year. The BHF’s runners, who are raising £3 million in funding, will include De Val Lab postdoctoral researcher Dr Alice Neal.
21 January 2022
A department-wide image competition has yielded a range of stunning images showcasing the diversity and breadth of DPAG's science. Three prize winners and eight commended pictures are announced.