Nicole Coggins, a PhD student in the labs of David Segal and Luis Carvajal-Carmona, has been awarded the 2016 Barbara Horwitz & John Horowitz Molecular, Cellular and Integrative Physiology Award. She will use the $1800 travel grant to visit Peggy Farnham’s lab at the University of Southern California to receive training in Circular Chromosomal Confirmation Capture paired with High-Throughput Sequencing, or 4C-seq, in order to better characterize interactions between gene promoters and non-coding regions. In her application, Nicole described the implications of her project:
‘Traditionally, the study of physiology has focused on the relationship between a protein’s structure and its function as a method of understanding its greater role within a tissue. The proper functioning of a set of proteins leads to the maintenance of the normal physiological homeostasis in which the tissue can function as a whole. As Next Generation Sequencing (NGS) has become more accessible, functional genomics has become a new and important aspect in our understanding of a tissue’s function with the identification of specific sequences within the genome that ultimately control expression of its critical proteins. Variations within these sequences can lead to changes in protein structure, causing changes in function and, more broadly, changes in the physiological state of a tissue. These dysregulations are often the basis of disease. While many protein-coding variants have been identified and shown to function in disease, many more variants located in the non-protein coding regions of the genome have also been linked to disease via GWAS. That is to say, mutations that have seemingly no direct impact on protein structure appear to also be contributing to disease onset and progression. As more has become known about the non-coding portion of the genome, we have uncovered the existence of elements with the ability to regulate gene expression, often in a tissue specific manner. The emerging hypothesis in the field now is that some of the variants linked to a disease are located in essential regulatory elements for the tissue in question and may be affecting the regulatory control these elements exert on their target genes. Identifying and deciphering the mechanism of control these regulatory elements have in a given tissue type as well as the GWAS variants that are functioning to dysregulate their control is a significant and necessary task to more fully understand these disease states and how best to correct them.
To date, it remains a rigorous task to link specific regulatory elements to their target genes. Regulatory interactions within the cell are often dynamic in response to the external environment of the tissue and very little data exists to characterize regulatory elements de novo. To address this, Circular Chromosomal Confirmation Capture paired with High-Throughput Sequencing (4C-Seq) was developed in 2006. This technique allows the user to take a snapshot of all the physical interactions within and between chromosomes for a population of cells. The idea behind this method is that a physical interaction between a gene promoter and a non-coding region may be indicative of an important regulatory element in that region. Taken a step further, one can compare normal versus disease states and identify such interactions that occur in one state and not the other (only normal or only diseased), suggesting these unique interaction may be areas of dysregulated regulatory elements, and thus, causative dysregulated gene expression. This method offers data that is crucial both to the advancement of my research project and to increasing our understanding of the pathogenesis of common late-onset disease, such as CRC.’
In addition to the funds, her name will be inscribed on a plaque at the College of Biological Sciences.