Functional genomics of tissue-specific gene regulation
The research in my junior group centers on understanding global gene regulation responses, the mechanisms involved, and how perturbation of gene regulation leads to disease. To address these questions, we integrate sequencing-based functional genomics and computational analyses to afford unbiased insights into the molecular mechanisms underlying gene expression plasticity in mammals.
This TFM offer will give you exposure to a multidisciplinary research plan - our methodology includes both experimental generation of genome-wide profiles of regulatory activity and transcription levels (e.g. ChIP-seq and RNA-seq) and the downstream computational analyses. Therefore this opportunity would be best suited to students with a keen interest in both experimental and computational biology. Previous experience with functional genomics approaches and/or some programming skills (e.g. R/Bioconductor, python or Perl) would be an advantage.
Please contact me by email for informal enquiries and discussion of the projects outlined below.
Synopsis of current projects:
Our integrative approach asks three key questions relating to tissue-specific gene regulation:
Functional implications of conserved and evolutionarily dynamic heart enhancers
In the mammalian heart, genome-wide enhancer activities are characterised by low sequence conservation (1,2), rapid divergence between human and mouse (3) and considerable plasticity to stress stimuli (4,5) - these properties may partly explain why active enhancers in human heart tissue (6) incompletely annotate regulatory regions associated to cardiovascular disease (7,8).
We will employ a comparative genomics approach across a collection of mammalian species to measure in vivo deployment of gene regulatory elements in heart tissue and its stability across species. These experiments will identify heart enhancers with conserved and lineage-specific activity, their associated gene expression output and their relationship to human genetic variation in heart disease.
The impact of non-coding variation on myocardial function and heart disease
Most common genetic variation associated to complex disease falls within the non-coding regions of the human genome; however, a current frontier in Human Genetics is the functional interpretation of such disease-associated non-coding variants. Using the myocardium and its response to ischaemia as a model system, we will investigate how cardiovascular phenotypes in the heart are affected by human genetic variation, most of which resides in non-coding regions with potential regulatory function (9).
These experiments will combine in vivo and in vitro myocardial models in mouse and human to characterize the gene regulation response to pathological stress in the myocardium. Exploiting novel genome editing techniques, we will also test the impact of selected regulatory elements in the myocardial phenotype, with a focus on enhancers harbouring disease-associated variants in the heart.
Regulatory adaptations conducive to stress-resistance in African mole-rats
Physiological adaptations to a subterranean environment are among the most striking in the mammalian phylogeny: subterranean mole-rats display reduced aging, tolerance to hypoxia, and cancer resistance. These unusual phenotypes have prompted genomic sequencing of both the naked mole-rat and the Damaraland mole-rat, two species of subterranean rodents sharing many common physiological traits. African mole-rats also exhibit reduced cardiovascular aging (10), high expression of cardioprotective transcription factors (11) and resistance to cardiac anoxia (12). However, the regulatory regions driving such lineage-specific traits are largely unexplored.
Through a number of international collaborations, we are profiling genome-wide enhancer activity and transcription factor binding events in liver and heart samples from two species of African mole-rats (13). By leveraging my comparative genomics expertise and novel phylogenetic analyses approaches (14), these experiments will identify candidate regulatory adaptations conducive to stress-resistance in the heart. These will be functionally validated in primary fibroblasts or iPSCs from naked mole-rats and mice.
Research in my group combines comparative functional genomics, computational biology and molecular approaches to investigate the mechanistic connections between dynamic gene regulation and tissue function. These insights have the potential to reveal novel molecular mechanisms conducive to stress resistance in mammals, as well as inform interpretation of human non-coding variants associated to heart disease.
References:
1 Blow, M. J. et al. ChIP-Seq identification of weakly conserved heart enhancers. Nature genetics 42, 806-810, doi:10.1038/ng.650 (2010).
2 Nord, A. S. et al. Rapid and pervasive changes in genome-wide enhancer usage during mammalian development. Cell 155, 1521-1531, doi:10.1016/j.cell.2013.11.033 (2013).
3 Vierstra, J. et al. Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution. Science 346, 1007-1012, doi:10.1126/science.1246426 (2014).
4 He, A. et al. Dynamic GATA4 enhancers shape the chromatin landscape central to heart development and disease. Nature communications 5, 4907, doi:10.1038/ncomms5907 (2014).
5 Papait, R. et al. Genome-wide analysis of histone marks identifying an epigenetic signature of promoters and enhancers underlying cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America 110, 20164-20169, doi:10.1073/pnas.1315155110 (2013).
6 Roadmap Epigenomics, C. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317-330, doi:10.1038/nature14248 (2015).
7 Kessler, T., Vilne, B. & Schunkert, H. The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease. EMBO molecular medicine, doi:10.15252/emmm.201506174 (2016).
8 Munroe, P. B. & Tinker, A. Genome-wide association studies and contribution to cardiovascular physiology. Physiological genomics 47, 365-375, doi:10.1152/physiolgenomics.00004.2015 (2015).
9 Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190-1195, doi:10.1126/science.1222794 (2012).
10 Grimes, K. M., Reddy, A. K., Lindsey, M. L. & Buffenstein, R. And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat. American journal of physiology. Heart and circulatory physiology 307, H284-291, doi:10.1152/ajpheart.00305.2014 (2014).
11 Lewis, K. N. et al. Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proceedings of the National Academy of Sciences of the United States of America 112, 3722-3727, doi:10.1073/pnas.1417566112 (2015).
12 Park, T. J. et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 356, 307-311, doi:10.1126/science.aab3896 (2017).
13 Villar, D. et al. Enhancer evolution across 20 mammalian species. Cell 160, 554-566, doi:10.1016/j.cell.2015.01.006 (2015).
14 Dunn, C. W., Zapata, F., Munro, C., Siebert, S. & Hejnol, A. Pairwise comparisons across species are problematic when analyzing functional genomic data. bioRxiv, doi:https://doi.org/10.1101/107177 (2017).