Research Centers

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Motamedi Lab

Research topics include: RNA-mediated epigenetic gene silencing.

Program Affiliations

Mo Motamedi, PhD
Assistant Professor of Medicine
Harvard Medical School

Research Summary

Humans have a variety of different cell types, which perform a multitude of functions necessary for life. Interestingly, all cells within an individual share the identical set of genes. So how do cells acquire different identities and functions? Recent work has revealed that during development cellular identity is established and maintained by a process called epigenetics, a molecular memory system by which cells turn some of their genes on and off, establishing distinct gene expression patterns and cellular identities. Epigenetic mechanisms ensure that correct gene expression patterns are inherited during cell division so that stable cell identities can be maintained throughout development. In cancers, cells lose their ability to retain their correct identity and display aberrant gene expression patterns. Epigenetic aberrations occur at all stages of malignancies, from tumor formation to metastasis. The Motamedi laboratory uses the powerful model system of the fission yeast to explore this problem. Our goal is to understand the precise molecular mechanisms involved in regulating epigenetics in an effort uncover novel targets for fighting cancers.

Read the Motamedi Lab's Annual Report in Full

Mo Motamedi, PhD
Principal Investigator

Group Members

  • Isadel Calvo Arnedo, PhD
  • Michael Cummings
  • Ian Hill, BSc*
  • Richard Joh, PhD
  • Jasbeer Singh Khanduja, PhD
  • Mo Motamedi, PhD
  • Christina Palmieri, BSc
  • Aditi Shukla, BSc*

*Graduate Student

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 aberrations have been shown to contribute to all stages of oncogens is 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 research has led to the discovery of highly conserved protein families and chromatin marks which are now being targeted for therapeutic or diagnostic purposes.The left image depicts RNA-mediated epigenetic gene silencing at the fission yeast centromeres, during which nascent long non-coding(lnc) RNAs, tethered to chromatin, act as platforms for the recruitment of silencing proteins. New synthesis of lncRNAs (shown as incorporation of new ribonucleotides) followed by lncRNA processing into short siRNAs (yellow RNA in the Red complex) lead to amplifications of the RNA silencing signal. The right image depicts the polymerization domain of one of the key silencing proteins, Tas3.

Non-coding RNAs and chromatin
The initial discovery that non-coding RNAs play a central role in epigenetic inheritance was made in the fission yeast, S. pombe. Since then, work from several laboratories has demonstrated the conservation of this mechanism in nearly all eukaryotes from plants to humans. Our model in pombe posits that non-coding 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 humans, a very similar mechanism operates in which non-coding RNAs regulate gene expression by recruiting chromatin-modifying or RNA-processing factors to sites of transcription. Uncovering the molecular details of this mechanism is one of the most exciting fields of research in molecular biology.

In the Motamedi lab, we focus on the molecular contribution of non-coding RNAs and chromatin-binding, -modifying, and -remodeling complexes to epigenetic gene silencing. We use a combination of genetic, biochemical, cell biological, genomic and proteomic approaches to ask mechanistic questions about how epigenetic circuits 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 the contribution of the homologous proteins to epigenetic inheritance and, in the long run, to cancers in human cells.

DNA repair and genomic stability
In eukaryotic cells, the abundance of repetitive DNA sequences (centromeres, telomeres, rDNA, etc.) and the presence of an efficient recombination system pose a serious challenge to genomic stability. To maintain genomic stability, cells compact their DNA into heterochromatin, which prevents spurious recombination, thus stabilizing the genome. Cells defective in heterochromatin formation exhibit high rates of chromosome loss in mitosis, display genomic instability, and display increased mutation rates. In the Motamedi lab, we study the role of chromatin and non-coding RNAs in DNA repair and genomic stability. Our goal is to identify and study novel chromatin/repair proteins in pombe and, ultimately, to study their role in oncogenesis using cancer cell lines.

Overall, our goal is to harness the powerful genetic, biochemical and cell biological tools available in the fission yeast to drive novel discoveries in RNA-dependent chromatin biology and to examine the contribution of these pathways in oncogenesis.

 

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

Mo Motamedi, PhD

The Center for Cancer Research
Room 7-212
CNY 149, 13th Street
Charlestown, MA 02129

Phone: 617-726-0676
Email: mmotamedi@hms.harvard.edu

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