Cancer evolution and patient-derived xenografts

Since joining JAX, our lab has begun projects in patient-derived xenografts, a model system in which human tumors are engrafted and studied in NSG mice. JAX has developed >300 such models from cancer types including breast, lung, bladder, and others. Our lab is involved in a number of studies using these models to understand the genetic drivers of cancer and drug resistance, with a particular focus on tumor heterogeneity and evolution. In related previous work, our group developed methods to analyze which aspects of lipid content are important to cancer phenotypes (Kiebish et al 2008) as well as equilibrium and dynamic models to explain mechanistically the distributions of lipids found in normal and cancerous tissues using statistical inference approaches (Kiebish et al 2010; Zhang et al 2011; Zarringhalam et al 2012).

RNA-level gene regulation

Our group has been studying mechanisms of post-transcriptional gene regulation.  Most recently, in collaboration with Professor Susan Ackerman (JAX Mammalian Genetics) we have identified a mutation in a tRNA as a driver for neurodegeneration and shown that this phenotype is mediated by specific translational pausing at the codons complementary to the tRNA anticodon (Ishimura et al 2014). More broadly, we have been studying the functions and neutral evolutionary behavior of synonymous sites in coding sequences for more than a decade (Chuang and Li 2004; Chin et al 2005). We have shown for example that coding sequences are replete with binding sites for microRNAs, as well as other types of functional sequences such as exonic splicing enhancers. Such sites exhibit a strong selective pressure on the synonymous sites of coding regions (Kural et al 2009; Ding et al 2012; Ritter et al 2012). We are also developing approaches to clarify functional elements in RNA based on a combination of functional genomic, structural, and modeling approaches (Zarringhalam et al 2012).

Other topics in evolutionary functional genomics

Our lab has been interested in a variety of issues in molecular evolution related to the balance of functional and neutral pressures in genomes. For example, we have studied the evolution of transcriptional enhancers. Our lab has collaborated with Professor Su Guo at UCSF to study conserved noncoding elements (CNEs), sequences with conservation far beyond what would be expected by neutral mutation in vertebrate intergenic regions. We developed computational approaches to identify and analyze CNEs and also experimentally investigated the functions of ~200 CNEs in developing zebrafish embryos (Li et al 2010). We have studied the relative importance of cis- and trans- regulatory effects on the functional behavior of enhancers (Ritter et al 2010) and have also shown experimentally that transcriptional enhancers can be embedded within coding sequences of vertebrate genes (Ritter et al 2012). Other interests have included gene expression evolution (Busby et al 2011) and evolution of mutation rates. For example, one puzzle is why mutation rates are uniform in some species, such as the sensu stricto yeasts, while rates vary by location in other species, such as mouse and human. We have found that all mammalian species have regional mutation biases, typically on a scale of several megabases. In contrast, all yeasts have uniform mutation rates, with the exception of the Candida clade (Fox et al 2008; Chuang and Li 2004; Chuang and Li 2007; Chin, Chuang, and Li 2005). In species where the mutation rate is non-uniform, we have been interested in questions such as what structural or sequence features affect mutation rates (Imamura et al 2009) and whether gene locations have evolved to synergize with mutational heterogeneity.

Chromatin interactions and its 3D structure play a major role in regulating gene expression by bringing together regulatory elements that are distal on the linear genome in close physical proximity with each other. Investigators at the JAX 4D Nucleome Center at The Jackson Laboratory for Genomic Medicine in Farmington, CT have pioneered genomic technologies for genome-wide profiling chromatin interactions. The JAX 4D Nucleome Center is seeking enthusiastic, highly-skilled computational and experimental post-docs to generate and analyze human chromatin interaction datasets in integration with other genomics and genetics datasets. 

Job Description 

Our center is seeking multiple postdoctoral researchers to develop computational and genomic approaches for understanding 3D genome biology under the light of diverse genomic and genetic information. We are seeking self-motivated, independent individuals who are interested in building their own career paths; however, postdoctoral fellows are expected to coordinate with and report to the PI responsible for the research area(s) addressed by their project. The fellows will develop research projects in one or more areas of focus: 

• 3D genome mapping and imaging technologies 
• Application of nano-engineering toward genomic methodologies 
• Computational modeling of 3D genome architectures 
• Building regulatory networks at multiple layers including gene expression, epigenetic, and chromatin data 
• Integrating regulatory interactions with genetic data 
• Mining and aligning chromatin interaction datasets in diverse human cell types 
• Functional perturbation of topological elements 

Desired Candidate Attributes 

The JAX 4D Nucleome Center is interdisciplinary and collaborative, and preference will be given to individuals with experience working in such an environment. 

For computational postdocs desired attributes include: 

• Strong problem-solving skills, creative thinking, and enthusiastic about science 
• Excellent communication skills and fully fluent spoken and written English 
• Familiarity with next generation sequencing data sets and pre-processing 
• PhD in a statistics/biostatistics or another computational field (CS, EE, Physics) with a strong foundation in statistics and data analyses 
• Excellent programming skills, preferentially with expertise in R and/or python and UNIX programming 
• Familiarity with network building, mining, alignment algorithms 
• Familiarity with bioinformatics resources, i.e., UCSC genome browser, NCBI.

For experimental postdocs desired attributes include: 

• Strong problem-solving skills, creative thinking, and enthusiastic about science 
• Excellent communication skills and fully fluent spoken and written English 
• Familiarity with next generation sequencing data sets and data generation 
• PhD in a genomics/genetics/biology or another relevant field 
• Expertise in cellular and molecular biology techniques 

Application Package 

Applications can be submitted to email address JAX4DN@jax.org as a single pdf document that contains: 1) a cover letter, 2) a full CV with a complete list of publications, 3) contact information for three references, and 4) a list of laboratory methods and computational skills mastered.

JAX 4D Nucleome Center Description 

Although the genome is typically thought of as a linear sequence, it is actually a dynamic three-dimensional structure. Gene loci and regulatory elements that are linearly distant—or even on separate chromosomes—may be brought in spatial proximity, and such interactions are of fundamental importance for understanding genome regulation. The ultimate goal of the JAX 4D Nucleome Center is to deliver a Nucleome Positioning System for the generation of complex chromatin interaction network maps in the context of 3D genome structures. Such maps will be used to monitor and reference the dynamics of individual genomic elements, providing context to better understand gene function and the effects of genetic variation on gene function. The scientific team is led by Yijun Ruan, Chia-Lin Wei, Jeff Chuang, and Duygu Ucar. 

The four major scientific goals of the JAX 4D Nucleome Center are to: 

• Develop and improve technologies for high-resolution and haplotype-specific 3D mapping. 
• Refine an integrative and comprehensive data-analysis platform (3D-NOME) for the study of nuclear architecture. 
• Elucidate the spatiotemporal regulation of 3D genome organization and function in human cells. 
• Use nuclear imaging and genome editing to structurally and functionally validate the 3D maps and predictions of regulatory interactions developed by the center.

The Jackson Laboratory Description 

The Jackson Laboratory (JAX) is an independent, non-profit organization focusing on mammalian and human genomics research to advance human health. The mission of its newest institute, The Jackson Laboratory for Genomic Medicine (JAX-GM), is to discover the precise genomic causes of disease and develop individualized diagnostics, treatments and cures by merging the Laboratory’s eight decades of research in mammalian genetics with those of our JAX-GM faculty and with the expertise of our clinical partners in Connecticut and the greater northeast. JAX-GM has amassed a diverse array of technologies, computing capabilities and core research and support services to facilitate genomic research. Our M.D./Ph.D.-level scientists have specialties in cancer, diabetes, immunology, stem cell biology, computational biology, genomic technologies, the human microbiome, and infectious disease.