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Read the Motamedi Lab 2017-2018 Annual Report
Mo Motamedi, PhDAssistant Professor of MedicineHarvard Medical School
Research in the Motamedi Lab focuses on a molecular memory system, called epigenetics which enables cells to develop stable identities during development or resist stress in response to environmental changes. Epigenetic mechanisms give cells new properties often by turning groups of genes on and off at a given time. A focus of the lab is studying the molecular machinery that permits cells to transmit this information (which genes are on and which genes are off) to progeny cells upon division. Another focus for the lab is cellular dormancy. Lately, scientists have discovered that a major reason for cancer resistance and recurrence is that a small number of dormant cancer cells originating from the primary tumor disperse throughout the body. These cancer cells are long-lived and can exit dormancy forming tumors years after remission. None of the existing therapies target dormant cancer cells. By studying dormancy, we strive to develop drugs that specifically neutralize these cells, which may help in addressing this critical knowledge gap in cancer therapy.
Mo Motamedi, PhDPrincipal Investigator
Epigenetic changes are stable and heritable alterations to gene expression patterns without concomitant mutations in the responsible genes. Disruption to epigenetic regulation leads to aberrant gene expression patterns, which underlie a variety of human maladies, including all cancers. Epigenetic defects have been shown to contribute to all stages of oncogenesis from initiation to metastasis. Understanding how epigenetic circuits are established, maintained and inherited at the molecular level is critical for the development of novel targets and therapeutic tools in cancer therapy. Most of what is known about the molecular mechanism of epigenetic inheritance comes from decades of research in model organisms such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Drosophila melanogaster. This has led to the discovery of highly conserved proteins which are now being targeted for therapeutic or diagnostic purposes in cancers. Using the fission yeast as a model our work is chiefly focused on understanding how changes to eukaryotic chromatin are made, maintained and propagated, and how these changes establish alternative cellular states particularly in response to environmental stress.
Noncoding RNAs and chromatin
A model about how long and small noncoding RNAs mediate epigenetic inheritance of chromatin states was proposed in the fission yeast. It posits that noncoding RNAs, tethered to chromatin, provide a platform for the assembly of RNA-processing and chromatin-modifying proteins, leading to transcriptional regulation of the neighboring genes. In addition to acting as platforms, RNA molecules target chromatin regulatory proteins to specific chromosomal regions. These principles now have emerged as a conserved mechanism by which noncoding RNAs partake in epigenetic inheritance of chromatin states and regulate gene expression globally. Recent work in cancer has revealed that regulation of epigenetic states by noncoding RNAs is intimately associated with all stages of oncogenesis. Thus uncovering the molecular details of this mechanism are likely to lead to development of new targets for cancer treatment.
In the Motamedi lab, we study how noncoding RNAs and chromatin complexes cooperate to mediate epigenetic gene silencing. We use a combination of genetic, biochemical, cell biological, genomic and proteomic approaches to ask mechanistic questions about the establishment of epigenetic states. Because many of the proteins involved in this process are highly conserved among eukaryotes, we will apply this knowledge to investigate how the homologous proteins regulate epigenetic inheritance in human cancers. For example, latest data have identified several chromatin and noncoding RNAs whose genome-wide arrangements in response to stress play a central role in adaptive responses. This work revealed a new function of heterochromatin proteins and the emergence of small noncoding RNAs, which orchestrate the genome-wide deployment of heterochromatin factors in response to long-term stress. This pathway regulates the expression of a set of developmental, metabolic and cell cycle genes, required for cell survival under persistent stress. In collaboration with several groups, we are now testing whether this pathway also helps cancer cells resist radiation and chemotherapy.
The Motamedi Lab at the Massachusetts General Hospital (MGH) Cancer Center and Harvard Medical School (HMS) has vacancies for two highly motivated Postdoctoral Research Fellows. The Fellow will have simultaneous academic appointments at HMS and MGH and contribute to ongoing research exploring the molecular mechanisms by which small and long non-coding RNAs contribute to the establishment of epigenetic states in response to stress using yeast and mammalian cells as models. These projects will explore mechanisms of RNAi-mediated silencing, RNA turnover, antisense transcription, and chromatin biology. The ideal candidates have (or will have) productive Ph.D. publication records, compatible with procuring external funding, with training in tissue culture, molecular biology, biochemistry, and/or cell biology. Because the Fellows will generate large scale genomic or proteomic datasets from yeast and/or human cells, previous experience with handling large datasets is a plus, but not required.
The laboratory is grounded in basic research and is working closely with the clinical researchers at MGH Cancer Center and HMS communities. The Cancer Center is composed of a vibrant milieu of world-class basic and clinical researchers, creating an exceptional environment for accelerating basic biology discoveries into clinical research.
See the cover story of the Dec 15th issue of Molecular Cell entitled “Survival in Quiescence Requires the Euchromatic Deployment of Clr4/SUV39H by Argonaute-Associated Small RNAs” for latest research (doi: 10.1016/j.molcel.2016.11.020).
Please email a one-page cover letter, CV, and contact information of three references to:Mo Motamedi, PhDMassachusetts General Hospital Cancer CenterHarvard Medical School Room 7.212, 149 13th street, Charlestown, MA email@example.com
View all publications from the Motamedi Lab.
Joh RI, Khanduja JS, Calvo IA, Mistry M, Palmieri CM, Savol AJ, Hoi Sui SJ, Sadreyev RI, Aryee MJ, and Motamedi M. 2016. Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by argonaute-associated small RNAs. † Mol Cell 64: 1088-1101.
Khanduja JS, Calvo IA, Joh RI, Hill IT, Motamedi M. 2016. Nuclear noncoding RNAs and genome stability. Mol Cell 63: 7-20.
Cummings MT*, Joh RI*, Motamedi M. 2015. PRIMED: PRIMEr Database for deleting and tagging all fission and budding yeast genes developed using the open-source Genome Retrieval Script (GRS) PLoSONE 10(2):e0116657.
Li H*, Motamedi M*, Yip C, Wang Z, Walz T, Patel DJ, Moazed D. 2009. An alpha motif at Tas3 C terminus mediates RITS cis-spreading and promotes heterochromatic gene silencing. ††Mol Cell 34: 155-167.
Motamedi M, Hong EE, Li X, Gerber S, Denison C, Gygi S, Moazed D. 2008. HP1 proteins from distinct complexes and mediate heterochromatic gene silencing by non-overlapping mechanisms. Mol Cell 32: 778-790.
Motamedi M*, Verdel A*, Colmenares S*, Gerber S, Gygi S, Moazed D. 2004. Two RNAi complexes, RDRC and RITS, physically interact and localize to non-coding centromeric RNAs. †††Cell 119: 789-802.
*Co-authors † This paper was the cover story in Molecular Cell and featured in Boston Magazine †† This article was previewed in Dev Cell. 16: 630-632, 2009 ††† This article was the cover story in Cell
Mo Motamedi, PhD
The Center for Cancer Research
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