In this episode of the Epigenetics Podcast, we talked with Mo Motamedi from the Center for Cancer Research at Massachusetts General Hospital about his work on RNA-mediated epigenetic regulation.

The Interview starts with Dr. Motamedi sharing his personal journey into the realm of biology, sparked by a familial inclination towards science and a challenge to excel in a field that initially felt daunting. His passion was ignited during a genetics class, as he recognized the quantitative nature of the discipline amidst the evolution of modern techniques like qPCR and high-throughput sequencing.

Dr. Motamedi goes on to articulate the importance of understanding the interplay between genetics and broader biological systems, emphasizing that an insightful grasp of evolution is vital for decoding cellular mechanisms. He reflects on his time in a postdoctoral lab under Danesh Moazed, investigating RNA interference (RNAi) and its unexpected nuclear roles, contributing significantly to the understanding of how RNAi is involved in gene silencing via chromatin interaction.

As his narrative unfolds, Dr. Motamedi provides deep insights into his own lab's work, which focuses on the establishment and maintenance of epigenetic states and their implications in cancer epigenetics. He discusses groundbreaking discoveries related to RNAi and heterochromatin, detailing experiments that unveil how specific proteins contribute to transcriptional and post-transcriptional gene silencing. A pivotal theme emerges: the complex dynamics of genome evolution and chromatin organization can be reshaped under various biological contexts, including the quiescent state of cells under stress.

Moreover, the discussion traverses recent publications from Dr. Motamedi's lab, revealing how they identify long non-coding RNAs that function as silencers at centromeres, an essential mechanism that aids in the establishment of heterochromatin independently of RNAi. His findings advocate for the idea that well-structured genome organization can lead to more efficient gene regulation, which can also be crucial in therapeutic contexts for various cancers.

Motamedi, M. R., Hong, E. J., Li, X., Gerber, S., Denison, C., Gygi, S., & Moazed, D. (2008). HP1 proteins form distinct complexes and mediate heterochromatic gene silencing by nonoverlapping mechanisms. Molecular cell, 32(6), 778–790. https://doi.org/10.1016/j.molcel.2008.10.026

Joh RI, Khanduja JS, Calvo IA, Mistry M, Palmieri CM, Savol AJ, Hoi Sui SJ, Sadreyev RI, Aryee MJ, and Motamedi M. Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by argonaute-associated small RNAs. † Mol Cell. 2016; 64: 1088-1101.

J. S. Khanduja, R. I. Joh, M. M. Perez, J. A. Paulo, C. M. Palmieri, J. Zhang, A. O. D. Gulka, W. Haas, S.P. Gygi, M. Motamedi. RNA quality control factors nucleate Clr4/SUV39H and trigger constitutive heterochromatin assembly. Cell 2024. 187: 3262-3283. *Equal contributions

R. I. Joh, M. S. Lawrence, M. J. Aryee, M. Motamedi. Gene clustering drives the transcriptional coherence of disparate biological pathways in eukaryotes. bioRxiv 2023. doi: 10.1101/2021.04.17.440292 *co-corresponding authors.

J. S. Khanduja, M. Motamedi. Protocol for the development and use of spike-in control for chromatin immunoprecipitation (ChIP) of chromatin-binding proteins. Star Protocol 2025. 6: 104007.

J. S. Khanduja, M. Motamedi. Protocol for chromatin immunoprecipitation of chromatin-binding proteins in Schizosaccharomyces pombe using a dual-crosslinking approach. Star Protocol 2025. 6: 103695.

Evolutionary Forces Shaping Mammalian Gene Regulation (Emily Wong)

Chromatin Evolution (Arnau Sebé-Pedrós)

The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier)

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