How Chromatin Marks Shape Transcription Factor Function (Luke Isbel)

In this episode we speak with Luke Isbell, Senior Research Fellow and group leader at Adelaide University and the South Australian immunoGENomics Cancer Institute. We discuss his work on transcription factors, chromatin, and how epigenetic marks on histones can influence transcription factor binding and function, with a focus on p53 and chromatin-based ways its activity can be silenced in cancer cells.

We also talk about how he became interested in biology, starting from growing up in rural Australia and later being introduced to epigenetics through Professor Emma Whitelaw. He describes how that experience shaped his path through honours and PhD training, and how his interest in biology developed into a long-term focus on chromatin and gene regulation.

He explains his PhD work on mouse mutagenesis screens and the transcriptional repressor WIS, which was identified in a screen for genes with epigenetic function. We discuss how that work connected WIS to regulation of clustered genes in the brain and showed the value of forward genetic screening in mice.

We then turn to his postdoctoral work in Switzerland with Dirk Schübeler, where he moved toward more mechanistic and reductionist chromatin biology. He describes the value of combining wet-lab and dry-lab work, and how that approach helps connect data generation with hypothesis testing.

Finally, we discuss his current lab in Adelaide, where he studies p53 cofactors, transcription factors, and how cofactors may help interpret chromatin marks in a tissue-specific way. He also reflects on the use of AI in science and on the importance of critical thinking, and closes by emphasizing the need to be kinder to people in academia.

References

• Luke Isbel, Lexie Prokopuk, Haoyu Wu, Lucia Daxinger, Harald Oey, Alex Spurling, Adam J Lawther, Matthew W Hale, Emma Whitelaw (2016) Wiz binds active promoters and CTCF-binding sites and is required for normal behaviour in the mouse eLife 5:e15082. https://doi.org/10.7554/eLife.15082
• Michael, A. K., Grand, R. S., Isbel, L., Cavadini, S., Kozicka, Z., Kempf, G., Bunker, R. D., Schenk, A. D., Graff-Meyer, A., Pathare, G. R., Weiss, J., Matsumoto, S., Burger, L., Schübeler, D., & Thomä, N. H. (2020). Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science, 368 (6498), 1460–1465. https://doi.org/10.1126/science.abb0074

Related Episodes

• Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)
• Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)
• The Impact of Sequence Variation on Transcription Factor Binding (Sven Heinz)

Contact

• Epigenetics Podcast on Mastodon
• Epigenetics Podcast on Bluesky
• Dr. Stefan Dillinger on LinkedIn
• Active Motif on LinkedIn
• Active Motif on Bluesky
• Email: podcast@activemotif.com