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RNA editing: innate immunity and human disease

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Transcriptional adaptation couples past experience and future sensory responses

Sensory adaptation allows neurons to minimize responses to persistent or repetitive stimuli, thereby emphasizing novel cues. Traditionally, it is thought that the periphery is a stable messenger of the outside world, while the brain flexibly adapts to changes in the environment. In the olfactory system, olfactory sensory neurons (OSNs) in the nose detect odors through odorant receptors and each OSN expresses only one receptor out of >1000 in mice and ~300 in humans. These OSNs have been thought to reliably respond to the same stimuli in the same way irrespective of their experience. By using single cell RNA-sequencing and in vivo calcium imaging, we recently revealed that OSNs adapt to the environment by reconfiguring their transcriptomes over timescales of hours to days. We find that each of the ~1000 receptor-defined mouse OSN subtypes harbors a distinct transcriptome. The content of each subtype-specific transcriptome includes >70 functional genes relevant to converting odor-receptor binding to action potentials, e.g., GPCR signaling factors and ion channels, and is precisely determined by interactions between the expressed odorant receptors and the environment. Critically, we find the patterns of functional gene expression predictably influences future odor responses. This discovery identified a novel form of adaptation and revealed unexpected flexibility in peripheral sensory codes. It also suggests a general model in which transcriptional variation within a single cell type reflects activity history of individual cells and contributes to optimize their functions. I will also briefly discuss about our ongoing work to comprehensively characterize odor representations at the periphery and examine how they are transformed in the brain.

Host: Dr. Patrick McGrath

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Mathematical modeling and genomics of cancer networks: applications to drug resistance and transcriptional reprogramming

How does the intracellular network of cancer cells give rise to the changes in cell state that lead to drug resistance and transcriptional reprogramming? In this talk, I will tell you about how we have tackled this question using approaches from the fields of systems biology (by iterating mathematical models and experiments), mathematical modeling / network theory (by developing computational methods to analyze models), and cancer genomics (by analyzing multi-omic datasets with rich clinical annotations). In particular, I will talk about three projects, one for each of these approaches. In the first, we built and experimentally tested a model of the signaling network underlying resistance to PI3K-alpha inhibitors in breast cancer. In the second, we developed a network theory framework to identify controller nodes in a mathematical model. In the third, we identified genomic and transcriptomic drivers of resistance to CDK4/6 inhibitors in metastatic breast cancer. Finally, I will give a brief overview of my proposed research program on leveraging both mathematical modeling and cancer genomics to study drug resistance in breast cancer.

Host: Dr. Greg Gibson

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Understanding the genetics of complex traits through statistical integration of genetic and genomic data

Understanding the genetics of human traits requires data that capture different aspects of the mechanisms. Genome-wide association studies (GWAS) have identified variants associated with thousands of traits. Functional genomic data such as transcriptomics can reveal underlying genes and cell types. Integrating different sources of data is crucial for gaining biological insights but poses great challenges for statistical analysis. We developed two statistical methods for integrative analysis of genetic and genomic data. First, I will introduce a new method for integrating GWAS data across many traits. A joint analysis of 116 traits characterized the variation of pleiotropy across the genome and linked it to several functional genomic signatures. Our analysis identified variants with highly trait-specific effects for the first time. Second, I will describe a new method to identify genes that show differential allele-specific expression (ASE) using single-cell RNA-seq data. ASE is a powerful tool to study cis-regulatory effects and can reveal the molecular mechanisms underlying variant-trait associations. Application of this method identified 657 genes that are dynamically regulated during endoderm differentiation. These genes can play an important role in early-life diseases. Finally, I will discuss future directions.

Host: Dr. Greg Gibson

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Animal movement in a changing world

Benjamin Van Doren studies the responses of migratory birds to environmental change. His research spans spatial and population scales and unites ecology, evolution, behavior, and conservation. Dr. Van Doren earned a PhD in Zoology from Oxford University, and he has received achievement awards from the American Ornithological Society, Linnean Society of London, and Zoological Society of London. In this talk, he will focus on how light pollution and human-dominated landscapes influence migrants’ ecology and behavior, and how migratory birds adapt to change via both plasticity and evolution. He will also discuss how new machine learning techniques and modeling approaches are pushing ecology forward while facilitating opportunities for conservation action.

Host: Dr. Mark Hay

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Legacies of stress: eco-evolutionary consequences of transgenerational & carryover effects in coastal systems

Phenotypic plasticity is a critical component of organisms’ responses to environmental change. My seminar will focus on a major component of my research program – “legacy effects,” or how past environmental experiences shape organism phenotypes, the mechanisms of these changes, and the consequences for communities and ecosystems. We will explore how parental experience with predators influences fitness and physiology in intertidal snails and how early life exposure to climate change stressors impacts oyster growth and nitrogen storage, a critical ecosystem service. By asking questions across scales, my work reveals new insights into how legacy effects shape patterns and processes in marine systems.

Host: Dr. Mark Hay

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"Past and present impacts of humans on tropical mammals"

We are at the precipice of the 6th mass extinction in Earth’s history and the only mass extinction that humans have caused. Given that biodiversity provides critical services for humanity, including food, clean water, carbon storage, and disease regulation, understanding how and why biodiversity is lost in non-random ways is important for both basic and applied research. In this talk, I will describe both past and present impacts of humans on tropical mammal communities. I will show how after human colonization, food webs globally lost more complexity from extinctions than would be expected by chance. Then, using unparalleled field data from camera traps deployed systematically in national parks throughout the tropics, I will share how my research group has demonstrated that humans are currently affecting the distribution of terrestrial mammals and birds worldwide. Even though protected areas are critical strongholds for wildlife conservation, ensuring the effectiveness of existing protected areas for conserving threatened species is both critical and urgent.

Host: Dr. Mark Hay

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Probing the Link between Microbial Diversity and Ecosystem Responses to Environmental Change

Microorganisms comprise most of the biodiversity on earth and perform critical functions that propel and maintain the planet’s life-sustaining biogeochemical cycles. Deciphering the mechanistic links between microbial eco-evolutionary dynamics and biogeochemical processes is key to understanding ecosystem responses to a changing world. A critical consideration in this regard is microbial adaptation to environmental change in complex natural systems, which is intricately linked to diversity within communities.  In this presentation, I will discuss the functional consequences of microbial diversity in natural systems, and the mechanisms by which co-occurring microbes partition niche space in geochemically fluctuating environments. To this end, I will focus on two microbial groups: archaea of the phylum Thaumarchaeota and the bacterial phylum Acidobacteria. These groups comprise up to 40 and 60% of the community in marine and terrestrial systems, respectively, and consist of oligotrophic microbes that play key roles in the global carbon and nitrogen cycles. I will draw parallels between the ecophysiology of the two groups and discuss the functional consequences of their diversification and niche differentiation on nitrogen and carbon transformations in marine and terrestrial ecosystems. I will further highlight the utility of dynamic natural systems and controlled perturbation experiments as study systems to probe microbial diversification patterns along environmental gradients. The presentation will conclude with current and future research focused on extending these approaches to specific global change scenarios aimed at developing a mechanistic understanding of microbial responses to environmental change and their consequences for nutrient cycling in a changing world.

Host: Dr. Joel Kostka

Quantitative effects on gene expression levels (dosage) underlie much of the genotype-to-phenotype pathway. In this talk, I will introduce “analog genomics,” which seeks to combine quantitative experimental and computational tools to understand gene regulation in human variation and disease. I will first discuss genetic studies of variation in human face and brain shape that revealed a key role for transcription factors (TFs) acting in facial progenitor cells. I will then describe an experimental approach to precisely modulate TF dosage and its application in dissecting the role of the dosage-sensitive TF SOX9 in craniofacial variation and disease. Future work will build upon these findings to understand mechanisms dictating dosage sensitivity and robustness in transcriptional networks across diverse developmental contexts.