From human-free supermarket check-outs to autopiloted cars, the modern world is rapidly moving towards automation. In the most recent advance, a rabble of robotic researchers has applied related technological tricks to epigenetic assays to “autopilot” high-throughput chromatin profiling and provide a clinical tool that may support optimized treatment choices in leukemia patients.
Specifically, a technology-driven team programmed by lab head Steven Henikoff (Fred Hutchinson Cancer Research Center, Seattle) aimed to fully automate the “cleavage under targets and tagmentation” (CUT&Tag) and “cleavage under targets and release using nuclease” (CUT&RUN) techniques to profile histone modifications and DNA binding factor occupancy in cells and tissues. As a proof-of-concept, these fully automated authors explored the epigenetic profiles at target sites for oncogenic proteins (or oncoproteins) formed by the fusion of the KMT2A histone lysine methyltransferase with other chromatin regulators occurring in specific leukemias.
Let’s hear from Janssens and colleagues about how this autopiloted chromatin profiling platform may “self-drive” leukemia patients to better treatments in the clinics:
- A standard liquid handling robot allows the full automation of CUT&RUN and CUT&Tag to provide a highly economical, consistent, and high-throughput means of chromatin profiling of leukemic cells
- A requirement for only thousands of cells makes this technique relevant for the screening of patient samples
- The application of “AutoCUT&Tag” demonstrates that bivalent chromatin domains marked by both H3K4me3 and H3K27me3 coincide with KMT2A oncoprotein binding sites
- The integration of single-cell CUT&Tag highlights cell-to-cell heterogeneity in some KMT2A oncoprotein target sites (i.e., differing patterns of active and repressive chromatin within a tumor sample)
- This heterogeneity may support the differential susceptibility to specific anticancer agents, which may foster therapeutic resistance
- “AutoCUT&RUN” revealed the affinity of distinct KMT2A oncoproteins with specific cofactors from a large transcriptional complex
- A subset of leukemia samples characterized by initiating RNA polymerase II binding and the presence of H3K4me3 enrichment in the bodies of KMT2A oncoprotein target genes display elevated sensitivity to the Menin inhibitor VTP50469
Overall, these findings suggest that integrating automated chromatin profiling tools with ongoing developments in single-cell CUT&Tag technology within clinical trials may help to further describe epigenomic heterogeneity within patient samples, predict those patients that will respond adequately to a specific therapeutic agent, or even identify novel therapeutic vulnerabilities.
Set the controls to automatic and autopilot over to Nature Genetics, November 2021.