Mutations of Gene Regulatory Elements in Human Disease (Nadav Ahituv)

In this episode of the Epigenetics Podcast, we talked with Nadav Ahituv from University of California, San Francisco about his work on mutations of gene regulatory elements in human disease.

Using massively parallel experiments, his lab revolutionized functional genomics by studying the impact of transcription factor binding sites on gene expression. His groundbreaking technology deciphered the regulatory language of gene expression by exploring transcription factor combinations, spacing, and orientation. By delving into the influence of DNA shape and gene topology, Nadav Ahituv's research provides a comprehensive understanding of gene regulation at the molecular level, shedding light on the complexity of genetic interactions.

The conversation delves into specific cases involving enhancers, gene sequencing, and 3D genomic structure, highlighting the impact of critical elements such as CTCF sites on gene expression. Discussions of haploid insufficiency and its implications for human health, using CRISPR technology to enhance gene expression, offer new possibilities for treating genetic diseases. Explorations of leptin-responsive regulatory elements in the hypothalamus and liver-associated transcription factors provide insights into metabolic regulation and gene expression networks in different tissues.

The episode also explores the epigenomic landscape, the evolution of methods from bulk approaches to single-cell analyses, and the role of AI and machine learning in deciphering complex genetic patterns. The conversation transitions to a unique study of bat embryonic development, dietary differences, and their implications for understanding wing development and metabolism in different bat species.

References

• Ahituv, N., Zhu, Y., Visel, A., Holt, A., Afzal, V., Pennacchio, L. A., & Rubin, E. M. (2007). Deletion of ultraconserved elements yields viable mice. PLoS biology, 5(9), e234. https://doi.org/10.1371/journal.pbio.0050234

• Matharu, N., Rattanasopha, S., Tamura, S., Maliskova, L., Wang, Y., Bernard, A., Hardin, A., Eckalbar, W. L., Vaisse, C., & Ahituv, N. (2019). CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science (New York, N.Y.), 363(6424), eaau0629. https://doi.org/10.1126/science.aau0629

• Ushiki, A., Zhang, Y., Xiong, C., Zhao, J., Georgakopoulos-Soares, I., Kane, L., Jamieson, K., Bamshad, M. J., Nickerson, D. A., University of Washington Center for Mendelian Genomics, Shen, Y., Lettice, L. A., Silveira-Lucas, E. L., Petit, F., & Ahituv, N. (2021). Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia. Nature communications, 12(1), 2282. https://doi.org/10.1038/s41467-021-22470-z

• Georgakopoulos-Soares, I., Deng, C., Agarwal, V., Chan, C. S. Y., Zhao, J., Inoue, F., & Ahituv, N. (2023). Transcription factor binding site orientation and order are major drivers of gene regulatory activity. Nature communications, 14(1), 2333. https://doi.org/10.1038/s41467-023-37960-5

• Gordon, W. E., Baek, S., Nguyen, H. P., Kuo, Y. M., Bradley, R., Fong, S. L., Kim, N., Galazyuk, A., Lee, I., Ingala, M. R., Simmons, N. B., Schountz, T., Cooper, L. N., Georgakopoulos-Soares, I., Hemberg, M., & Ahituv, N. (2024). Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas. Nature communications, 15(1), 12. https://doi.org/10.1038/s41467-023-44186-y

Related Episodes

• Ultraconserved Enhancers and Enhancer Redundancy (Diane Dickel)

• Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos)

• Enhancer-Promoter Interactions During Development (Yad Ghavi-Helm)

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