Professor Tom Owen-Hughes FRSE
Chromatin remodelling and cancer epigenetics
Chromatin remodelling enzymes related to the yeast SWI/SNF complex have been found to be among the most frequently mutated tumour suppressors. Interestingly, mutations to different subunits drives cancers of different tissues. Prior, to the emergence of their importance in cancer these chromatin remodelling complexes were known to act to configure nucleosomes at key regulatory elements to enable appropriate expression of many genes. This raises the question why do ubiquitously acting transcriptional regulators act as tissue specific tumour suppressors?
Answering this question is now assisted by new tools to study acute loss of function. These include inhibitors (Papillion et al., 2018), PROTACS (Farnaby et al., 2019) and targeted protein degradation (Blümli et al., 2021). In addition to being powerful research tools, these models are of therapeutic interest as some tumours are vulnerable to loss of paralogs (Hoffman et al., 2014).
Figure 1 Acute and chronic changes following loss of ARID1A. ARID1A is a subunit of a multi-subunit complex that acts to generate accessible chromatin principally at enhancer elements. When this subunit is degraded changes to chromatin structure, association of the coactivator EP300 and transcription are observed after just 2 hours (middle panel). Over subsequent days indirect transcriptional changes are observed at many more genes. These mimic a knock-out of the ARID1A gene. From Blümli et al., 2021.
We have used the auxin degron system to degrade subunits of SWI/SNF complexes within minutes. This has revealed that the chromatin changes occurring following loss of function affect expression of relatively few genes (Figure 1). Directly affected genes are differentially expressed after 2 hours, but in the days that follow widespread indirect changes are detected. We now reason that if we understand more about how this pathway operates, we will identify new targets that when inhibited will prevent the development of cancer.
Our ongoing work is interdisciplinary and involves engineering human stem cells for acute loss of function. We then work with our excellent stem cell facility to generate organoid models relevant to tissue specific cancers. We use high throughput DNA sequencing to characterise chromatin and transcriptional changes. We then work with computational biologists to perform integrative analysis of these time course measurements. The aim is to reveal the pathway from loss of function to development of a cancer phenotype. Longer term we aim to work with chemists to inhibit this pathway and hopefully provide new entry points for these tissue specific cancers.
Blümli S, Wiechens N, Wu MY, Singh V, Gierlinski M, Schweikert G, Gilbert N, Naughton C, Sundaramoorthy R, Varghese J, Gourlay R, Soares R, Clark D, Owen-Hughes T. Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription. Cell Rep. 2021 Nov 2;37(5):109943. doi: 10.1016/j.celrep.2021.109943. PMID: 34731603; PMCID: PMC8578704.
Sundaramoorthy R, Owen-Hughes T. Chromatin remodelling comes into focus. F1000Res. 2020 Aug 20;9:F1000 Faculty Rev-1011. doi:10.12688/f1000research.21933.1. PMID: 32864100; PMCID: PMC7445562.
Flaus A, Downs JA, Owen-Hughes T. Histone isoforms and the oncohistone code. Curr Opin Genet Dev. 2021 Apr;67:61-66. doi: 10.1016/j.gde.2020.11.003. Epub 2020 Dec 4. PMID: 33285512.
Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhöfer-Wölfer K, Wöhrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu MY, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB, Ciulli A. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol. 2019 Jul;15(7):672-680. doi: 10.1038/s41589-019-0294-6. Epub 2019 Jun 10. Erratum in:Nat Chem Biol. 2019 Jul 2;: PMID: 31178587; PMCID: PMC6600871.
Sundaramoorthy R, Hughes AL, El-Mkami H, Norman DG, Ferreira H, Owen-Hughes T. Structure of the chromatin remodelling enzyme Chd1 bound to a ubiquitinylated nucleosome. Elife. 2018 Aug 6;7:e35720. doi: 10.7554/eLife.35720. PMID: 30079888; PMCID: PMC6118821.