A central question in biology is how a single genome can give rise to the hundreds of distinct cell types that compose an organism. To achieve this task, the genome must be tightly and selectively regulated. Much of this regulation is thought to come from chromatin, a layer of proteins that cover and package our DNA or genomic code. In a recent report that was the cover article for Cell, Dr. Ahmad S. Khalil and his team of researchers at Boston University describe an experimental platform to engineer, design, and control this layer of regulation, which is distinct to eukaryotes. The team engineered molecular tools that could bind specific locations in the genomic code and alter the local structural and chemical properties of chromatin, thus affecting the expression of genes. This research introduces a new framework to engineer cells in organisms like yeast and mammalian cells. It also supports the use of synthetic biology approaches to control and harness this complex regulatory chromatin layer for future uses in disease intervention, biopharmaceutical production, and basic research.
This research study is the product of a collaborative effort between Dr. Ahmad Khalil and fellow Boston University colleague Dr. James Collins. It is supported by Khalil’s CAREER award from the Division of Molecular and Cellular Biosciences. The CAREER Award Program is a Foundation-wide activity that offers the National Science Foundation’s most prestigious awards in support of junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organizations. The Khalil group has a history of introducing undergraduate and high school students to synthetic biology through summer research, in addition to hosting regular outreach and education activities focused on molecular biology and microfluidics.
A common source of molecular damage in organisms is through oxidation, which can occur through natural processes, such as aerobic respiration, and from exposure to toxins such as ultraviolet radiation or pollution. Molecules that cause oxidation, known as reactive oxygen species (ROS), cause damage to proteins and DNA in cells and create a cell state of oxidative stress. In a recent study published in PLOS Genetics, MCB-funded investigator Dr. Amy Schmid and her team of researchers at Duke University describe the hierarchical dynamic response to oxidative stress in archaea, a single-cell model organism which has a gene regulation system similar to bacteria and eukaryotic cells.
This dynamic response controls the expression of over 100 genes whose RNA and protein products work to repair cellular damage caused by exposure to ROS. A key characteristic of this response is the presence of regulatory proteins which facilitate a sequential process to control damage repair. First, the proteins target genes to address cellular damage, then target genes to restore normal cellular function. Because the regulatory proteins involved in the response to stress are of a hybrid ancestry, these findings suggest that the evolution of gene networks may have been influenced by environmental forces, such as oxidative stress. When asked about the broader implications of her work, Dr. Schmid responded, “The results demonstrate that regulatory proteins of ancient evolutionary ancestry in archaea provide mechanistic links between various stress responses as well as between the regulatory network and its effects on cell physiology (e.g. transcriptional regulation, metabolic activity, growth rate, and cell morphology). These results have made significant progress in understanding gene network function, how it may be integrated with cell physiology, and how the network may evolve in response to stress throughout the tree of life”
The reported research was conducted by a team of varied experience and comprised graduate student Peter Tonner, research associates Adrianne Pittman and Kriti Sharma, and undergraduate researcher Jordan Gulli. As a result, trainees were integrated into research that addressed open questions in the fields of microbiology and mathematical modeling. In addition, the Schmid group hosts undergraduate students from Historically Black Colleges and Universities for summer research experiences and teaches a weeklong immersion course for high school students in collaboration with K-12 teachers. In this course, an interdisciplinary team of computational and experimental graduate students teaches high school students about mathematical modeling of microbial growth and response to oxidative stress.