RegulatorySystemsMedicine

Key Research Areas

• Genome evolution
• Gene regulation
• Genomics and Bioinformatics

Research Overview

Our main goal is to understand how changes in the genome sequence control transcriptional change during developmental, regenerative and evolutionary processes. By applying regulatory genomics and computational strategies, we aim to understand how genetic and epigenetic signals are propagated to gene expression, and how this in turn has consequences on higher biological processes. To do this, we produce high-throughput data and use statistical models but also go beyond to dry lab to generate molecular data in different organisms to address fundamental questions that have consequences in both health and disease.

There are 3 key projects underway in the Regulatory Systems Laboratory, led by A/Prof Emily Wong;

1. Tracing regulatory evolution

Most disease loci lie in non-coding regions of the genome and are enriched at enhancers and promoters. Enhancers are rapidly evolving and most enhancers in humans cannot be mapped to the mouse. We use novel concepts, computational and molecular approaches to identify conserved enhancers and understand their mechanism of function and mode of change. This research was recently published in Science.

2. Regeneration genomics

We aim to study the systems biology of heart regeneration to better understand the restorative mechanisms of cells in damaged hearts in vertebrates. Regeneration has been studied in a range of animals but the zebrafish is the most extensively-studied vertebrate model for heart regeneration. We use quantitative strategies to understand how regulatory systems change during the repair process.

3. Regulatory variation during ageing

We are using single cell multi-omics approaches to study how tissues change in ageing animals

1. Cornejo P, Petrova V, Zhang X, Young R, Wong ES (2024) Enhancer turnover is associated with DNA replication timing. Nature Communications 15:3451
2. Wong ESW (2024) The nuance in DNA-transcription factor interactions. Nature Reviews Molecular Cell Biology 25:251 [Commentary]
3. Achinger-Kawecka J, Stirzaker C, Chia K, Portman N, Campbell E, Du Q, Laven-Law G, Nair S, Yong A, Wilkinson A, Clifton S, Milioli H, Schmitt A, Wong ES, Hickey T, Lim E, Clark S (2024). The potential of epigenetic therapy to target the 3D epigenome in endocrine-resistant breast cancer Nature Structural and Molecular Biology. 31(3):498-512
4. Smith G, Ching W, Cornejo P, Wong ESW* (2023) Decoding enhancers with machine learning and high-throughput discovery. Genome Biology 12;24(1):116 [Review]
5. Ferreira Silva L, Senan S, Bejan M, Córdova C, Smith C, Gabbita S, Wenteler A, Nussbaum Z, Reddy A, Li Z, Patel Z, Weber N, Tunjic TM, Wong ES*, Meuleman W*, Pinello L*. (2023) DNA-Diffusion: Generative diffusion models for enhancing gene expression control through synthetic regulatory elements. ISMB/ECCB (Intelligent Systems for Molecular Biology/ European Conference on Computational Biology)
6. Subramanian S, Thoms J, Huang Y, Cornejo P, … Wong ES, Göttgens B, Alinejad Rokny H, Wong JWH, Pimanda JE (2023). Genome-side transcription factor-binding maps reveal cell-specific changes in the regulatory architecture of human HSPCs. Blood, 142:1448-1462
7. Chiang I, Humphrey D, Mills R, Kaltzis P, Pachauri S, Braus M, Saha D, Wu Z, Young P, Sim C, Davidson T, Hernandex-Garcis A, Scott D, Porrello E, Wong ES, J Hudson, Red-Horse K, del Monte Nieto G, Francois M (2023) Sox7-positive progenitor cells establish coronary arteries and instructs ventricular compaction. EMBO Reports 24:e55043
8. Marjaneh M, Kirk E, Patrick R, Alankerage D, Humphreys D, Del Monte-Nieto G, Janbandhu V, Doan T, Dunwoodie S, Wong ES, Moran C, Martin I, Thomson P, Harvey R (2023) Quantitative trait and transcriptome analysis of genetic complexity underpinning cardiac interatrial septation in mice using an advanced intercross line. eLife 12:e83606
9. Cornejo-Paramo P, Roper K, Degnan S, Degnan B, Wong ES (2022) Distal regulation, silencers and a shared combinatorial syntax are hallmarks of animal embryogenesis. Genome Research 32:474-487
10. Fennell KA, Vassiliadis D, Lam L, Martelotto LG, Balic J, Wang Q, Hollizeck S, Weber T, Semple T, Miles D, MacPherson L, Kat L, Wong ES, Dawson S, Naik S, Dawson MA (2022) Identifying non-genetic determinants of malignant clonal fitness at single cell resolution. Nature 601:125-131
11. Flochay S^, Wong ES^, Zhao B^, Viales R, Thomas-Cholier M, Thieffry D, Garfield D, Furlong E (2021) Cis-acting variation is common across regulatory layers but is often buffered in developmental programs Genome Research 31:211-224 [doi:10.1101/gr.266338.120]
12. Wong ES, Zheng D, Tan S, Bower N, Garside V, Vanwalleghem G, Gaiti F, Scott E, Hogan B, Kikuchi K, McGlinn E, Francois M, Degnan B (2020) Deep conservation of the enhancer regulatory code in animals Science 370:6517 [doi: 10.1126/science.aax8137]
13. Friedman CE, Nguyen Q, Lukowsk S, Helfer A, Chiu H, Miklas J, Levy S, Suo S, Han J, Osteil P, Peng G, Jing Nm Baillie G, Senabouth A, Christ A, Bruxner T, Murry C, Wong ES, Ding J, Wang Y, Hudson J, Ruohola-Baker H, Bar-Joseph Z, Tam P, Powell J, Palpant NJ (2018) Single cell transcriptomic analysis of cardiac differentiation from human PSCs reveals HOPX-dependent cardiomyocyte maturation Cell Stem Cell 23:586-598 [doi: 10.1016/j.stem.2018.09.009]
14. Jasinska AJ, Zelaya I, Service SK, Peterson C, Cantor R, Choi O, DeYoung J, Eskin E, Fairbanks L, Fears S, Furterer A, Huang Y, Ramensky V, Chmitt C, Svardal H, Jorgensen M, Kapln J, Villar D, Aken B, Flicek P, Nag R, Wong ES, Blangero J, Dyer T, Bogomolv M, Benjamini Y, Weinstock G, Dewar K, Sabatti C, Wilson R, Jentsch D, Warren W, Coppola G, Woods R, Freimer N (2017) Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate Nature Genetics 49:1714-1721 [doi: 10/1038/ng.3959]
15. Wong ES, Schmitt B, Thybert D, Marioni J, Ferguson-Smith A, Odom DS, Flicek P (2017) Interplay of cis and trans mechanisms driving transcription factor binding, chromatin, and gene expression evolution Nature Communications 8:1092 [doi: 10.1038/s41467-017-011037-x]
16. Wong ES, Thybert D, Schmitt B, Stefflova K, Odom DS, Flicek P (2015) Decoupling of evolutionary changes in transcription factor binding and gene expression in mammals Genome Research 25:167-78 [doi: 10.1101/gr.177840.114]