Student Research

Nano-environmental Engineering

Measuring, modeling, & modulating the chromatin nano-environment for transcriptional regulation

Nano-environmental EngineeringAdvances in molecular biology have made it easier than ever to explore the functions of the human genome. We tend to now think of the functional properties of the genome with respect to the activities each gene carries out and the overarching molecular regulators of that behavior. Comparatively underexplored is the physical organization of the genome and its effects on the functions of genes. In much the same way that the organization of a city influences our behavior (e.g. driving in Boston vs. Chicago, public transit in Los Angeles vs. NYC), the structure of the genome has a major impact on molecular behavior. To study the effects of physical organization on genomic function requires the capability to measure the relevant structures in real-time, develop models of how this organization alters behavior, and test them experimentally. My research has therefore focused on all of these aspects – helping to develop microscopic techniques that are nanoscale sensitive to image the physical structure of the genome within seconds, developing mathematical models that account for the role of the measured physical structure on processes such as gene expression, and testing these predictions using molecular techniques.

While the understanding of the role physical forces play on genomic function is at its earliest stages, we have been able to apply this approach to develop compounds that control the physical structure of the genome in order to manipulate global patterns in gene expression, so called “Macrogenomic Engineering.” My goal is to develop this physico-chemical Macrogenomic Engineering as a complement to existing gene editing tools: while gene editing techniques work at the level of the linear genetic code and thus individual genes, the regulation of the genomic structure affects the global patterns of gene expression. As most diseases are inherently genomic and multifactorial in nature, the combination of these techniques may eventually allow us to address diseases where the global reprogramming of gene expression plays a role, such as cancer, inflammation, and neurodegeneration. – Luay Almassalha

Forming Brain Tissue

Uncovering how integrin is needed for cells to come together and assemble organs in regeneration

Forming Brain TissueThe use of stem cells to regenerate damaged tissue has the potential for far-reaching medical applications. Certain animals have evolved the ability to harness their stem cells for complete regeneration after injury and are models for understanding natural mechanisms of tissue repair. The flatworm planarian Schmidtea mediterranea is famous for its ability to regenerate after removal of any body part because of robust mechanisms to control the activity of its potent adult stem cells. My research uses planarians as a model system to study how stem cells differentiate into specialized cell types and how their progeny assemble to form functional organs, such as the brain, during regeneration. We found that β1-Integrin, a cell surface molecule involved in adhesion to the extracellular matrix, is required for the proper organization of brain tissue in planarian regeneration. Inhibition of the β1-Integrin gene caused regenerating planarians to generate disorganized brains in which neurons aggregated with each other randomly rather than forming distinct and symmetric brain lobes. Intriguingly, these aggregates resemble organoids, a type of synthetic tissue that human stem cells form in petri dishes in the absence of a natural environment for growth. Planarians depleted of integrin activity also produced excess brain neurons that were placed at abnormal locations, suggesting that integrin signaling is additionally required to determine appropriate numbers and positions of mature brain neurons formed through regeneration. Together these results showed that integrin signalling regulates planarian stem cell activity to control the organization and scale of tissues formed during regeneration. – Nicolle Bonar

Genomics in C. elegans

Leveraging genomic and computational approaches to understand biology

cook reflectionI have a long-standing interest in the application of novel computational tools to answer important biological questions. During my PhD studies in the IBiS program at Northwestern, I focused on understanding the genomes of a tiny translucent nematode called Caenorhabditis elegans. Specifically, I studied the role genetic differences play in making each individual in a population distinct from one another. My projects have focused on three areas. First, I characterized natural differences in the genomes of wild strains by developing bioinformatic pipelines to identify single nucleotide variants (SNVs) and other genomic features. Second, our lab measures correlations of these genetic differences with physical differences (using a technique known as genome-wide association) to identify which specific genetic differences make individuals distinct from one another. For example, we identified a specific genetic difference that contributes to the regulation of the ends of chromosomes (telomeres) across the natural population. Finally, I developed tools that make the study of natural variation across the species easier for the scientific community. Towards this end, I created an interactive web portal - The C. elegans Natural Diversity Resource - available at elegansvariation.org, and developed a command-line utility for processing genome sequence data known as VCF-kit. – Daniel Cook

What Are Methanobactins?

The biosynthesis, regulation, and transport of an unusual family of metal-binding natural products

What Are Methanobactins?Methanotrophic bacteria – bacteria for which the only source of carbon is methane – are a major area of research for the Rosenzweig group. The enzymes responsible for the oxidation of methane to methanol are metalloenzymes, and metal homeostasis plays a major role in governing methane oxidation. My project focuses on the natural product family known as methanobactins. These compounds are secreted from the cells of methanotrophic bacteria, and once outside of the cell, they bind copper with high affinity. Copper-bound methanobactins are then re-admitted to the cell and the internalized copper is ultimately incorporated into some of the metalloenzymes responsible for methane oxidation. Over my time in the Rosenzweig group, my work has provided insight into how these unusual natural products are biosynthesized, how they are transported out and into the cell, and how their production is regulated by the availability of copper. – Grace Kenney

Seeing Nucleosomes Up Close

High-res mapping of nucleosomes in embryonic stem cells with new biochemical and computational tools

What Are Methanobactins?Nucleosomes affect transcription primarily by regulating the accessibility of DNA-binding proteins to the underlying DNA sequence. Understanding how nucleosomes regulate transcription requires knowing precisely where they are positioned. Recent advances in sequencing technologies have made it possible to map the detailed locations of nucleosomes across the genomes of a multitude of organisms and cell types. These genome-wide nucleosome maps have significantly expanded our understanding of the role of nucleosome positioning and dynamics in eukaryotic transcriptional regulation. My research focuses on the development of chemical and computational approaches to charting the nucleosome landscape in mammalian cells. Recently, we implemented a chemical nucleosome mapping strategy in mouse embryonic stem cells and uncovered new insights into the dynamic interplay between nucleosomes, transcription, and splicing. – Lilien Voong