Active DNA Demethylation and Its Role in Cancer Progression (Kunal Rai)

In this episode of the Epigenetics Podcast, we talked with Kunal Rai from MD Anderson Cancer Center about his work on active DNA demethylation and its role in cancer progression.

A major part of the conversation covers his postdoctoral work on active DNA demethylation. He describes how he identified an AID-MBD4-based mechanism, later supported by GAD45, and how this work showed a role for DNA demethylation in early neuronal differentiation and in colon cancer initiation.

We then discuss his move into his own lab and his work on melanoma progression. He explains how he used broad epigenomic profiling, chromatin state analysis, and 3D chromatin methods to study enhancers and chromatin organization, and how these approaches helped reveal changes linked to cancer progression.

Another topic is his work on epigenetic regulators such as RNF2 and KMT2D. He describes findings on polycomb and trithorax-related factors, including tumor-suppressive roles for KMT2D in melanoma and lung cancer, and how KMT2D loss affects cell phenotype and metabolism.

Finally, we talk about lab organization, collaboration, and newer technologies. He says his group works across multiple cancer types and increasingly includes immunology, single-cell methods, spatial epigenomics, and clinical translation, while still using ChIP-seq, CUT&RUN, and CUT&Tag where appropriate.

References

Fiziev, P., Akdemir, K. C., Miller, J. P., Keung, E. Z., Samant, N. S., Sharma, S., Natale, C. A., Terranova, C. J., Maitituoheti, M., Amin, S. B., Martinez-Ledesma, E., Dhamdhere, M., Axelrad, J. B., Shah, A., Cheng, C. S., Mahadeshwar, H., Seth, S., Barton, M. C., Protopopov, A., Tsai, K. Y., … Rai, K. (2017). Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression. Cell reports, 19(4), 875–889. https://doi.org/10.1016/j.celrep.2017.03.078
Terranova, C. J., Tang, M., Maitituoheti, M., Raman, A. T., Ghosh, A. K., Schulz, J., Amin, S. B., Orouji, E., Tomczak, K., Sarkar, S., Oba, J., Creasy, C., Wu, C. J., Khan, S., Lazcano, R., Wani, K., Singh, A., Barrodia, P., Zhao, D., Chen, K., … Rai, K. (2021). Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy. Cell reports, 36(3), 109410. https://doi.org/10.1016/j.celrep.2021.109410

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