Motamedi

Motamedi Lab

Research topics include: RNA-mediated epigenetic gene silencing.

Overview

Mo Motamedi, PhD
Assistant Professor of Medicine
Harvard Medical School

Research Summary

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 changes often works by adjusting which genes are on or off at a given time in a cell and ensures the stable transmission of this information to progeny cells upon division. It also creates special structures that protect our DNA from mutation and genomic instability. Loss of these DNA structures is found in all cancers and is linked to increase in mutation rate and genome instability. Using the fission yeast as a model, the lab studies the molecular mechanism by which epigenetic states are established and propagated. Because of the conservation of the proteins involved in this process in yeast and human cells, this work may lead to the discovery of several novel targets for treating cancers.

Read the Motamedi Lab's Annual Report in Full

Group Members

Mo Motamedi, PhD
Principal Investigator

Group Members

  • Isadel Calvo, PhD
  • Richard Joh, PhD
  • Jasbeer Khanduja, PhD
  • Christina Palmieri, BSc

Research Projects

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 the battle against cancer. 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 work has led to the discovery of highly conserved proteins which are now being targeted for therapeutic or diagnostic purposes in cancers.

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 how epigenetic states are established, maintained and reprogrammed in cells. 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 from the lab have identified several chromatin and noncoding RNAs whose genome-wide arrangements in response to stress play a central role in adaptive responses. This work has revealed a novel function for these proteins and noncoding RNAs, and appears to be conserved from yeast to human cells. In collaboration with several groups, we are now pursuing these targets in several human cancers.

Argonaute (Ago1) guides histone H3 lysine 9 methylation (H3K9me) to euchromatic regions in quiescence. In these artist renditions by Mo Motamedi and Katia Popova, as cells enter quiescence (moon), they load Ago1 (ships) with euchromatic small RNAs to mediate Quiescent-induced Transcriptional Repression (Q) of a set of euchromatic genes. Exosome activity separates heterochromatic (blue) from euchromatic (yellow) regions. When entering quiescence, the exosome barrier opens, permitting euchromatic transcripts (differently colored dots) to become substrates for RNAi degradation. Ago1, acquiring new color (sRNAs) as it crosses the exosome barrier, targets Q to the corresponding color in euchromatin.

 

Research Positions

Postdoctoral Research Fellow

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, PhD
Massachusetts General Hospital Cancer Center
Harvard Medical School
Room 7.212, 149 13th street,
Charlestown, MA 02129
mmotamedi@hms.harvard.edu

Publications

View all publications from the Motamedi Lab.

Selected Publications

Joh RI, Khanduja JS, Calvo IA, Mistry M, Palmieri CM, Savol AJ, Hoi Sui SJ, Sadreyev RI, Aryee MJ, and M. Motamedi. 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.

Joh RI, Palmieri CM, Hill IT,  Motamedi M. Regulation of histone methylation by noncoding RNAs.  Biochim Biophys Acta. 1839(12): 1385-94, 2014.

Li H*, Motamedi M*, Yip C, Wang Z, Walz T, D. J. Patel, D. Moazed. An alpha motif at Tas3 C terminus mediates RITS cis-spreading and promotes heterochromatic gene silencing. †Mol Cell. 34: 155-167, 2009.

Motamedi M, Hong EE, Li X,  Gerber S, Denison C, Gygi S, Moazed D. HP1 proteins from distinct complexes and mediate heterochromatic gene silencing by non-overlapping mechanisms. Mol Cell. 32: 778-790, 2008.

Motamedi M*, Verdel A*, Colmenares S*, Gerber S, Gygi S, Moazed D. Two RNAi complexes, RDRC and RITS, physically interact and localize to non-coding centromeric RNAs. ††Cell. 2004;119: 789-802.

*Co-authors
†This article was previewed in Dev Cell.  16: 630-632, 2009
††This paper was featured as the cover article

Contact

Contact Us

Mo Motamedi, PhD

The Center for Cancer Research

CNY 149, 13th Street Room 7-212 Charlestown, MA 02129,

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