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 establish stable fates during development or resist stress in response to environmental changes. Epigenetic mechanisms impart cells with 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. Recently, 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 unmet need in cancer therapy.

Read the Motamedi Lab's Annual Report in Full

Group Members

Mo Motamedi, PhD
Principal Investigator

Group Members

  • Alex Gulka, BSc
  • Junichi Hanai, PhD*
  • Richard Joh, PhD
  • Jasbeer Khanduja, PhD
  • Jose Lombana, BSc
  • Sunny Sharma, PhD

*Instructor in Medicine, HMS

Research Projects

Epigenetic changes are heritable, phenotypic alterations which occur without mutations to the underlying genes. Once triggered, these phenotypic changes persist through numerous cell divisions independently of the original inducing signal. Epigenetic changes are critical for the stable formation of cellular identities, upon which all developmental processes depend. Disruption to epigenetic regulation underlies a variety of human maladies, including cancers. In fact, epigenetic pathways can contribute toall stages of cancer progression, including initiation, metastasis, resistance and recurrence. Therefore, understanding the molecular mechanisms that establish epigenetic states is fundamental to the development of therapies that target the epigenetic components of cancers.

Often, but not always, epigenetic changes are concomitant with alterations to the chromatin state of underlying genes. Most of what is known about how chromatin states are altered in response to epigenetic triggers comes from decades of research in model organisms. These studies have revealed highly conserved protein families, which are now used for therapeutic or diagnostic purposes in cancers. The Motamedi lab uses the fission yeast as a model to understand how changes to eukaryotic chromatin are made, maintained and propagated, and how these changes establish alternative transcriptional programs particularly in response to persistent stress.

Noncoding RNAs and chromatin – partners in epigenetic regulation

One of the first models for how long and small noncoding RNAs regulate 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 (Motamedi et al 2004), leading to transcriptional regulation of the underlying genes. In addition to acting as platforms, RNA molecules also can function as trans-acting factors, targeting chromatin regulatory proteins to specific chromosomal regions. These principles now have emerged as conserved mechanisms by which noncoding RNAs partake in chromatin regulation in eukaryotes including in humans.

A focus of the lab is cellular quiescence (or G0). G0 is a ubiquitous cellular state in which cells exit proliferation and enter a state of reversible dormancy. Developmental programs, such as wound healing, or exposure to a variety of stress, such as starvation, can trigger entry into or exit from G0. G0 cells have distinct transcriptional programs through which they acquire new properties compared to their proliferative selves, including long life, thrifty metabolism and resistance to stress. Loss of G0 regulation results in defects in developmental and adaptive programs. How cells enter, survive and exit G0 is a critical question in basic biology, which is largely unexplored. To address this knowledge gap, we modeled G0 in fission yeast and showed that when cells transition to G0, new ncRNAs emerge which coopt and deploy constitutive heterochromatin proteins (histone H3 lysine 9 methyltransferase, Clr4/SUV39H) to several euchromatic gene clusters to regulate the expression of a set of developmental, metabolic and cell cycle genes. We show that this pathway is critical for survival and the establishment of the global G0 transcriptional program. This work revealed a new function of heterochromatin proteins and noncoding RNAs, which orchestrate the genome-wide deployment of heterochromatin factors in response to long-term stress. It also led to the proposal of several hypotheses that we are currently testing. Moreover, in collaboration with several groups, we have begun to test whether this pathway also plays an important role in cancer dormancy and treatment resistance.

The image depicts 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 (dark 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 Motamedi M. 2016. Survival in quiescence requires the euchromatic deployment of Clr4/SUV39H by argonaute-associated small RNAs. † Mol Cell 64: 1088-1101.

Laviolette LA, Mermoud J, Calvo IM, Olson N, Boukhali M, Huang D, Teh BT, Motamedi M, Haas W, IliopoulosO. 2017. Negative Regulation of EGFR Signaling by the Human Folliculin (FLCN) Tumor Suppressor Protein. Nature Commun 8:15866.

Khanduja JS, Calvo IA, Joh RI, Hill IT, Motamedi M. 2016. Nuclear noncoding RNAs and genome stability. Mol Cell 63: 7-20.

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

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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