Dr Hamish King, Lab Head | WEHI Researcher Profile

Q: Functional relevance of genetic variants in autoimmune disease

Autoimmune diseases are underpinned by immune cell dysfunction that can be impacted by inherited genetic variation. We recently used single-cell transcriptomics and epigenomics to map cell type-specific chromatin accessibility and gene expression at autoimmune genetic variant loci and found that many loci had specific regulatory potential in cells associated with the germinal centre (GC), a dynamic immunological structure where autoreactive B cells are regulated to prevent autoimmunity. We are now interrogating whether these autoimmune genetic variants are involved in regulating gene expression in GC cells with functional genomic assays on ex vivo culture systems and single-cell based screens.

Q: Disease-specific gene regulatory networks in autoimmunity

Building on findings in healthy patient datasets, and concurrent with detailed mechanistic studies, we want to understand whether the B cell response in patients with autoimmune disease is associated with disease-specific epigenetic dysregulation or regulatory element function. This question has been examined previously in peripheral blood-derived B cells populations, but whether such disease-specific epigenomic patterns exist in the GC response of patients with autoimmune disease has not been determined. This is especially important as the GC is a major site of immune cell fate decisions.

Q: Immune-specific chromatin pathways

Our current understanding of chromatin-based gene regulation in immune cells relies upon the function of ubiquitously-expressed epigenetic readers and writers. However, specific chromatin readers and writers are uniquely over-expressed or restricted to immune cell lineages. This project aims to identify such chromatin-associated factors and investigate how and where they interact with the epigenomes of different immune cell lineages. We leverage both in vitro and ex vivo immune cell culture methods, combined with cutting edge bulk and single-cell genomics to understand how normal, and disease-specific, gene regulatory networks are defined and controlled by chromatin readers and writers.

About

Hamish King completed his undergraduate and Honours at Flinders University in Adelaide, before moving to the United Kingdom to undertake his PhD training in molecular epigenetics at the University of Oxford with Prof Rob Klose. While there he studied how gene expression is regulated by chromatin-modifying complexes, and how sequence-specific transcription factors cooperate with chromatin remodellers to access and bind the genome. Following his PhD, Hamish was a Sir Henry Wellcome Postdoctoral Fellow in the lab of Dr Louisa James at the Blizard Institute, Queen Mary University of London, where he studied the transcriptional and epigenetic regulatory networks that determine B cell identity and function in the human immune system.

Building on these discoveries, Hamish joined WEHI as a Laboratory Head in 2022, where his team is focused on understanding how defects in the epigenetic control of gene expression are involved in human autoimmune disease.

To achieve this, the lab uses both experimental and computational approaches, combined with ex vivo immune cell cultures for human B cell maturation. We integrate results from our lab-based analyses with datasets from “real world” patient single-cell transcriptomic and epigenomic datasets, and vice versa, with the long-term aim to provide translational insights into how epigenetic dysregulation in the immune system is linked with disease.

Education

Grants and funding

Publications

Selected publications from Dr Hamish King

Massoni-Badosa R, Aguilar-Fernández S, Nieto JC, Soler-Vila P, Elosua-Bayes M, Marchese D, Kulis M, Vilas-Zornoza A, Bühler MM, Rashmi S, Alsinet C, Caratù G, Moutinho C, Ruiz S, Lorden P, Lunazzi G, Colomer D, Frigola G, Blevins W, Romero-Rivero L, Jiménez-Martínez V, Vidal A, Mateos-Jaimez J, Maiques-Diaz A, Ovejero S, Moreaux J, Palomino S, Gomez-Cabrero D, Agirre X, Weniger MA, King HW, Garner LC, Marini F, Cervera-Paz FJ, Baptista PM, Vilaseca I, Rosales C, Ruiz-Gaspà S, Talks B, Sidhpura K, Pascual-Reguant A, Hauser AE, Haniffa M, Prosper F, Küppers R, Gut IG, Campo E, Martin-Subero JI, Heyn H. An atlas of cells in the human tonsil. Immunity. 2024;57(2):10.1016/j.immuni.2024.01.006

Conde CD, Xu C, Jarvis L, Rainbow D, Wells S, Gomes T, Howlett S, Suchanek O, Polanski K, King H, Mamanova L, Huang N, Szabo P, Richardson L, Bolt L, Fasouli E, Mahbubani K, Prete M, Tuck L, Richoz N, Tuong Z, Campos L, Mousa H, Needham E, Pritchard S, Li T, Elmentaite R, Park J, Rahmani E, Chen D, Menon D, Bayraktar O, James L, Meyer K, Yosef N, Clatworthy, Sims P, Farber D, Saeb-Parsy K, Jones J, Teichmann. Cross-tissue immune cell analysis reveals tissue-specific features in humans. Science. 2022;376(6594):10.1126/science.abl5197

Kleshchevnikov V, Shmatko A, Dann E, Aivazidis A, King HW, Li T, Elmentaite R, Lomakin A, Kedlian V, Gayoso A, Jain MS, Park JS, Ramona L, Tuck E, Arutyunyan A, Vento-Tormo R, Gerstung M, James L, Stegle O, Bayraktar OA. Cell2location maps fine-grained cell types in spatial transcriptomics. Nature Biotechnology. 2022;40(5):10.1038/s41587-021-01139-4

King HW, Wells KL, Shipony Z, Kathiria AS, Wagar LE, Lareau C, Orban N, Capasso R, Davis MM, Steinmetz LM, James LK, Greenleaf WJ. Integrated single-cell transcriptomics and epigenomics reveals strong germinal center–associated etiology of autoimmune risk loci. Science Immunology. 2021;6(64):10.1126/sciimmunol.abh3768

King HW, Orban N, Riches JC, Clear AJ, Warnes G, Teichmann SA, James LK. Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics. Science Immunology. 2021;6(56):10.1126/sciimmunol.abe6291

King HW, Fursova NA, Blackledge NP, Klose RJ. Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes. Genome Research. 2018;28(10):10.1101/gr.237180.118

King HW, Klose RJ. The pioneer factor OCT4 requires the chromatin remodeller BRG1 to support gene regulatory element function in mouse embryonic stem cells. eLife. 2017;6:10.7554/elife.22631

Rose NR, King HW, Blackledge NP, Fursova NA, Ember KJ, Fischer R, Kessler BM, Klose RJ. RYBP stimulates PRC1 to shape chromatin-based communication between Polycomb repressive complexes. eLife. 2016;5:10.7554/elife.18591

Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LLP, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long HK, Sheahan TW, Brockdorff N, Kessler BM, Koseki H, Klose RJ. Variant PRC1 Complex-Dependent H2A Ubiquitylation Drives PRC2 Recruitment and Polycomb Domain Formation. Cell. 2014;157(6):10.1016/j.cell.2014.05.004

King HW, Michael MZ, Gleadle JM. Hypoxic enhancement of exosome release by breast cancer cells. BMC Cancer. 2012;12(1):10.1186/1471-2407-12-421