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Welcome to the Jaffrey Lab

at the Weill Cornell Medical College of Cornell University

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Research Opportunities in the Jaffrey Lab

Several positions are currently available:

Chemical Biology and Fluorescence Imaging Postdoctoral Positions

We believe that scientific breakthroughs are driven by novel enabling technologies.  A major goal of the Jaffrey laboratory is to use chemical biology and synthetic biology to create new imaging and optogenetic tools that reveal new insights into cellular function and disease.


As an example, our laboratory developed "RNA mimics” of green fluorescent protein.  These are RNA aptamer sequences that bind fluorophores that resemble the fluorophore in GFP, and switch them from a nonfluorescent state to a fluorescent state.  We developed RNAs that bind a series of GFP-related fluorophores, producing a palette of fluorescence emissions ranging from blue to red.  Much of our work has focused on “Spinach,” an RNA that emits a bright green fluorescence. We have tagged noncoding RNAs with Spinach, expressed these RNAs, and imaged them in living cells. These experiments have resulted in powerful and unprecedented insights into RNA trafficking in cells.

 

This work was described in a paper in Science (Paige, J.S., Wu, K.Y., Jaffrey, S.R. RNA mimics of green fluorescent protein, Science, 333:642-646, 2011), as well as several follow-up studies.

 

To understand cellular function, researchers need to image the highly dynamic changes in cellular metabolites and signaling events in living cells.  This requires novel types of biosensors that can detect the diversity of these signaling events.  At present, protein-based sensors have not been able to detect the diversity of cellular events that account for cellular function.  To overcome this problem, we are using RNA to create sensors.  RNA is highly plastic and can be molded into diverse shapes that bind and recognize cellular signaling molecules and metabolites.  We recently used this principle to fashion RNA into biosensors that fluoresce upon binding specific metabolites and proteins in the cell.   


The most useful aspect of these RNAs is that cells can be engineered to express them.  As a result, the cells directly report signaling events in cells based on their fluorescence.  We expect that these genetically encoded RNA-based sensors will form the foundation for a fundamentally novel technology that will rival or replace current FRET-based approaches.


This work was described in a paper in Science (Paige, J.S., Ngyuen-Duc, T., Song, W., Jaffrey, S.R. Fluorescence imaging of cellular metabolites with RNA. Science, 335:1194, 2012), as well a follow-up study in Nature Methods (Song, W., Strack, R.L., Jaffrey, S.R. Imaging bacterial protein expression using genetically encoded RNA sensors. Nature Methods, 10:873-5, 2013).  More recent papers have focused on new aptamers such as Broccoli and directed evolution technologies to evolve appetizers to function in mammalian cells.

  

We want creative and ambitious postdocs who are interested in projects that further develop and apply this novel and innovative technology.  For instance, we are developing new, brighter RNA-fluorophore complexes. For example we have developed “Carrot” and “Radish” RNA aptamers which bind fluorophores similar to the red fluorescent protein fluorophore, and which provide bright orange and red fluorescence. We are currently optimizing these tags for multiplexed imaging of RNA in cells.  Additionally, we are developing RNA-fluorophore complexes with new photophysical properties, including resistance to photobleaching and photoactivation. We are also developing DNA aptamers that mimic GFP.  We are also using Spinach to image fundamental molecular biology reactions, such as splicing, enabling RNA processing events to be monitored in living cells. Additionally, we are interested in using Spinach and Carrot to image the trafficking of novel non-coding RNA in cells in order to uncover their biological functions.  


For our sensor work, we are developing new RNA sensor microarrays to potentially detect dozens or hundreds of small molecules in a tissue sample at once. We are developing novel types of sensors to image diverse types of molecules, including proteins with specific post-translational modifications.  We are developing RNA-based sensors in order to image the dynamics of signaling and epigenetic modifications in cells.  These and a variety of other innovative projects are currently a major focus of the laboratory.  


Importantly, we do not exclusively develop new technologies.  We are also interested in using them to address questions in cell biology or signaling. Postdocs who are interested in both developing and applying new technologies are encouraged to apply. 

 

We have positions available for postdocs in projects that range from molecular biology, imaging, chemical biology, and synthetic chemistry.  Postdoctoral candidates who have expertise in imaging, microscopy, fluorescence, fluorescent proteins, synthetic biology, RNA biochemistry, or related areas are welcome to apply. Postdocs who have experience with synthetic chemistry, especially related to fluorescent dye synthesis are also encouraged to apply.

 



RNA Molecular Biology: N6-Methyladenosine Postdoctoral Positions

We recently discovered that in addition to the canonical nucleotides (A, C, G, U), mRNA also contains a fifth base,
 N6-methyladenosine (m6A).  m6A is a highly pervasive modified nucleotide and constitutes approximately 0.1% of all adenosine residues throughout the transcriptome.  Although m6A was detected in RNA nearly 40 years ago, it was never clear if m6A was found in mRNA or if it was found in other types of RNAs.  In 2012 we described a new next-generation sequencing approach, termed methyl RNA-immunoprecipitation sequencing (MeRIP-Seq), which allowed us to show for the first time that m6A is indeed a widespread base in mRNA. Using MeRIP-Seq, we showed for the first time that not only is m6A present within mRNA, but that it is found in nearly a quarter of protein-coding mRNAs. Thus, adenosine methylation represents a novel and relatively unknown mechanism of mRNA regulation with the potential to impact a substantial portion of the transcriptome.  

 

Although we found that m6A residues can be found anywhere in a transcript, m6A is predominantly found in either the 5’ regions of transcripts or near the stop codon. The highly selective localization of m6A in mRNAs suggests that m6A has an important role in regulating mRNA function. Furthermore, the localization of m6A in very distinct regions of transcripts suggests that multiple functions might exist for m6A, a possibility which further expands the potential influence of this widespread mark on gene expression.


Our work on m6A was described in a paper in Cell (Meyer, K.D., Saletore, Y., Zumbo, P., Elemento, O., Mason, C.E., Jaffrey, S.R.  Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons, Cell, 149:1635-1646, 2012), as well as a follow-up study performed in collaboration with Jen Bruning’s lab (University of Cologne) in Nature Neuroscience (Hess, M.E., et al.  The Fat Mass and Obesity Associated (Fto) Gene Regulates Activity of the Dopaminergic Midbrain Circuitry.  Nature Neuroscience, 16:1042-1048, 2013).   We recently developed an approach to directly map each m6A base at single nucleotide resolution in mRNA (Linder et al., Nature Methods, 2015). 


One of the major functions of m6A is to control a form of translation called "cap-independent" translation.  We showed that m6A is specifically deposited in the 5'UTRs of certain mRNAs, allowing those mRNAs to be translated when cap recognition of mRNAs is suppressed, such as in cell stress and disease states.  A major focus of our lab is to understand how m6A is targeted to 5'UTRs and how this novel form of m6A-directed translation functions to control normal and disease proteomes.


Furthermore, we are exploring other novel functions for m6A as well as other nucleotide modifications such as N6, 2'-O-dimethyladenosine (m6Am), which we recently mapped in the transcriptome (Linder et al.  Nature Methods, 2015).  We are using a variety of molecular biology, sequencing, bioinformatic, and chemical biology approaches to explore this novel form of mRNA regulation. The projects focus on revealing roles of m6A and m6Am in cancer, development, and signaling.


Our projects related to m6A provide a unique opportunity to explore a completely new area of RNA molecular biology.  Postdocs will have the opportunity to work on projects that will result in seminal papers that will provide the foundation for what will eventually become a major area of molecular biology research. Postdocs with expertise in molecular biology, especially pathways related to RNA (e.g. splicing, noncoding RNAs, transcription, etc) are encouraged to apply.



Neuroscience and RNA Biology Postdoctoral Positions

 

One major focus of our laboratory is to understand how protein expression is regulated in neurons.  Protein expression in synapses and axons is critical for synaptic plasticity, axon guidance, and for circuit formation.  Thus, precise regulation of protein synthesis is essential for neuronal function.  As a result, RNA-binding and RNA-regulatory proteins are often mutated in neurodevelopmental diseases such as autism, mental retardation, and schizophrenia.

 

Protein expression in synapses and axons is regulated by the process of “local translation,” which is the synthesis of proteins directly within synapses and axons using localized ribosomes and mRNAs. We have identified mRNAs that are present in growth cones, and provided the first evidence in 2005 for a specific mRNA that is required within axons for axonal guidance. Subsequent studies from our group identified novel signaling proteins that are synthesized in axons during axon guidance processes. Also, we have found that locally translated proteins are locally degraded through the ubiquitin-proteasome system. 

 

Recently we uncovered a novel form of regulation involving localized mRNA degradation.  We showed that axons and dendritic spines are highly enriched in RNA degradation machinery and that signaling pathways can act to induce RNA degradation.  Our findings suggest that a major mechanism to control protein expression is highly localized mRNA degradation, thereby limiting the repertoire of proteins that can by locally synthesized in axons.

 

Our work has been published in Cell, Nature, Neuron, Nature Cell Biology, and other journals.  To get an idea of our work, see:

 

Wu, K.Y., Hengst, U, Macosko, E., Cox, L., Urquhart, E., Jeromin, A., Jaffrey, S.R.  Local translation of RhoA regulates growth cone collapse. Nature, 436:1020-1024, 2005

 

Hengst, U., Deglincerti, A., Kim, H.J., Jeon, N.L., Jaffrey, S.R. Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein. Nature Cell Biology, 11:1024-30, 2009.

 

Cohen, M.S., Bas Orth, C., Kim, H.J. Jeon, N.L., Jaffrey, S.R. Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites. Proc. Natl. Acad. Sci. USA., 108:11246-11251, 2011.

 

Ji, S.-J., Jaffrey, S.R. Intra-axonal translation of SMAD1/5/8 mediates retrograde regulation of trigeminal ganglia subtype specification. Neuron, 74:95-107, 2012.

 

Colak, D., Ji, S.-J., Porse, B.T., Jaffrey, S.R.  Regulation of axon guidance by compartmentalized nonsense mediated mRNA decay. Cell, 6:1252-1265, 2013.

 

Curanovic, D., Cohen, M., Slagle, C.E., Singh, I., Leslie, C.S., Jaffrey, S.R. Transcriptome-wide profiling of stimulus-induced polyadenylation in living cells using a poly(A) trap. Nature Chemical Biology, 9:671-3, 2013.

  

A major goal of laboratory is to understand how signaling molecules selectively induce the translation and degradation of specific mRNAs.  One focus of our laboratory is to understand why proteins that control RNA degradation are enriched in growth cones and synapses, and to determine how RNA degradation pathways are regulated in response to synaptic signaling.  We suspect that precise control of RNA degradation might have major roles in synaptic plasticity and axon guidance.  We have also found that noncoding RNAs are enriched in synapses and growth cones.  However, it is not clear why these RNAs are targeted to these sites.  We suspect that noncoding RNAs may have major roles in synaptic function by regulating local RNA translation.  Lastly, we have recently discovered novel poly(A) polymerases in axons.  We think these proteins may be critical regulators of local translation.  We are exploring how these enzymes control mRNA translation.

 

These projects focus on understanding the molecular biology of mRNA translation and degradation in axons and dendrites.  Postdocs who have experience with molecular biology approaches will be well-suited to explore projects in this area.  Postdoc will have the opportunity to use novel viral tools and microfluidic strategies for studying axonal signaling and local translation, as well as proteomic methodologies for studying important signaling mechanisms in axons

 


 

The Jaffrey lab covers projects in diverse areas, including molecular biology, neuroscience, chemical biology, and imaging.  Postdocs get a unique opportunity to be exposed to research questions and techniques in the forefront of various fields.  This type of training environment is exceptionally valuable for individuals who are interested in pursuing careers in academia or scientific leadership positions in the pharmaceutical industry.


Each of the projects provide the opportunity for considerable creativity and innovation and applicants with these skills are also especially encouraged to apply.  The wide range of research topics in the Jaffrey lab makes it an excellent environment for interdisciplinary training.  The laboratory environment is highly collegial and interactive, so excellent written and oral communication skills are a must.

 

Cornell University's Weill Medical College is located in Manhattan's Upper East Side, immediately adjacent to the Sloan Kettering Institute and Rockefeller University. This "tri-institutional campus" includes several hundred principal investigators and postdocs, and has one of the highest densities of biomedical scientists in the world. This rich scientific environment provides unique and unparalleled research training opportunities, including research seminars given by leaders in science from throughout the U.S. and abroad, opportunities for collaborations, exposure to diverse research programs, and highly sophisticated core facilities.

 

Members of the Jaffrey lab have received prestigious fellowships, including the Damon Runyon, Life Sciences, EMBO, the NIH K99 Pathway to independence award.  After leaving the Jaffrey laboratory, former postdocs have been very successful.  Several have moved on to independent academic faculty positions throughout the United States, China and Europe.  Other laboratory members have moved on to leadership positions in Pharma or have started biotechnology-oriented companies.

 

Questions about the positions described here, and/or applications, comprising a CV, statement of research interests, and contact information for three references, should be e-mailed to Dr. Samie Jaffrey at jaffreylab2 at gmail.com.  A hard copy of the application is not recommended.

 


Graduate Students

The Jaffrey lab is open to graduate students with diverse interests, including Neuroscience, Pharmacology, Cell Biology, Chemistry, Genetics, and Developmental Biology.  Recent rotation students include those enrolled in the Tri-Institutional Chemical Biology Program, Computational Biology Program, and MD/PhD program.

Interested students should e-mail Samie Jaffrey to arrange a rotation.