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.

Research Positions

Postdoctoral Research Fellow

The Motamedi Lab at the Harvard/Mass General Center for Cancer Research has vacancies for two highly motivated Postdoctoral Research Fellows. The Cancer Center is composed of a vibrant milieu of world-class basic and clinical researchers, creating an exceptional environment for advancing molecular and clinical research in the battle against cancer. The Fellows will have an opportunity to study the molecular mechanism of chromatin and non-coding RNAs in epigenetic gene silencing, genomic stability and metabolism. The ideal candidates have productive Ph.D. publication records, compatible with procuring external funding, with expertise in molecular biology, genetics, biochemistry, genomic and/or proteomic techniques. Previous experience with using computational tools in analyzing large biological data sets is preferred, but not required. The Fellow will have simultaneous academic appointments at the Massachusetts General Hospital and Harvard Medical School. The Fellow will develop innovative genetic screens, in vivo and in vitro assays, combined with genomic and proteomic approaches, to study the contributions of histone modifications, chromatin remodeling factors, and non-coding RNAs in regulating critical pathways important for oncogenesis. The laboratory is grounded by a strong basic research focus, and will be working closely with the clinical researchers at the Cancer Center.


The Motamedi lab at the Harvard/Mass General Cancer Center is located within an outstanding research community with strong ties to the MGH, Harvard, and MIT communities. The Fellow will have extensive opportunities to participate in Boston-wide academic forums and seminar series.

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

Publications

View all publications from the Motamedi Lab.

Selected Publications

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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