Pranitha Vangala and colleagues build predictive model of gene expression
Pranitha Vangala, PhD, GSBS ’20, is lead author of a study published in the journal Molecular Cell, in which she and colleagues present a predictive model of gene expression.
“The goal of the study is to understand how gene expression regulation works. Gene expression is regulated by elements known as promoters and enhancers,” said Dr. Vangala, a postdoc in the lab of Manuel Garber, PhD, associate professor of molecular medicine, co-director of the Bioinformatics Core and co-author on the paper. “There has been a lot of effort to define what enhancer regions are, yet we are lacking information on how these enhancers regulate expression, which genes they regulate and how much they contribute to the regulation of a particular gene.”
Vangala, Dr. Garber and colleagues analyzed the role of enhancers, which are short regions of DNA that regulate when and where transcription of a particular gene will occur. To do so, they built a progression model framework to define the amount an enhancer contributes to a gene it regulates.
“We used 3D chromatin interactions mapped by a method called SPRITE, or ‘split pool recognition of interactions by tag extension,’ developed in our collaborator Mitchell Guttman’s lab at the California Institute of Technology. This helps us look at the activity from a single molecule resolution,” Vangala said. “We integrated SPRITE interactions into a statistical model that could be used to determine the quantitative impact of losing an enhancer, and what that does to a gene’s expression.”
Through the SPRITE high-resolution mapping, researchers were able to show genes that form stable enhancer-promoter (E-P) hubs have less cell-to-cell variability in gene expression. They were also able to identify transcription factors that regulate E-P interactions.
“This work is critical and novel in understanding diseases in humans. We know where enhancers are in our DNA, but we do not know which ones are working in a given cell or just how much they contribute to expression. Through this specific method, we can see which enhancers come in close contact with the promoters. To add to its complexity, we are also looking at how a given enhancer can interact with multiple promoters and establish several expression patterns,” said Garber.
These findings are also benefitting researchers within the UMMS community. John Harris, MD, PhD, associate professor of dermatology and director of the Vitiligo Clinic and Research Center, is working in collaboration with Vangala and her colleagues. He said this research and the tools it generates will help them better understand the underlying causes of skin diseases.
“We’ve actively been applying Dr. Vangala’s research to our own work to better understand vitiligo, an autoimmune skin disease that causes a loss of pigment in spots,” Dr. Harris said. “Vitiligo is influenced by our genes, so having this ability to understand the genome up close, to examine how it folds and how the distance between key elements plays a role in human disease, is a major opportunity for our department.”
Vangala earned her PhD in May 2020, serving as class speaker at the Graduate School of Biomedical Sciences virtual commencement ceremony. During the course of the COVID-19 pandemic, she finished her doctorate degree, advanced and completed her scholarly study and became a mother to a baby girl.
“It was certainly a challenging time, but I would not trade it for anything,” Vangala said. “I am so grateful for what this year has brought me, and I’m honored to now be a published scientist.”
The link to the full, published study can be found here.