NSF Postdoctoral Fellowship in Biology FY 2021: Analyzing the interplay of chromatin accessibility and transcription factor binding to decipher the cis-regulatory code

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2021, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment and Phenotypes. The fellowship supports research and training of the Fellow that will contribute to the area of Rules of Life in innovative ways. In order for an organism to properly function, expression of its genes must be tightly regulated by transcription factors (TF), proteins that bind a specific DNA sequence to control whether a gene is turned on or off.

Variants in DNA sequence can lead to mis-localization of TF, disruption of normal gene expression, and disease. Therefore, knowledge of the precise DNA sequence bound by TF and how the surrounding DNA sequences influence TF binding is necessary to gain a deep understanding of how genes are regulated. However, current methods only examine one of these components and require large amounts of starting material thereby limiting the model systems that can be studied.

Therefore, this project will focus on the development of a method (ChIP-next) that will provide comprehensive maps of TF binding sequences and the surrounding DNA landscape from low amounts of starting material. Results from this project will enhance our understanding of how TF interpret DNA sequence and how small changes in DNA sequence can have large impacts on mammalian development, disease, and evolution.

In addition to the research component, the Fellow will also provide scientific outreach to underrepresented Native American populations in Oklahoma.

ChIP-next will allow for the collection of chromatin accessibility and TF binding datasets from the same sample. In order to examine the dynamic interplay of chromatin accessibility and TF binding, ChIP-next will be performed at different time points on differentiating mouse embryonic stem cells (mESC) in culture. Furthermore, using a recently developed deep learning model, the Fellow will predict which DNA bases are most important for TF binding in both mESC and mouse embryos and how mutation of these sequences affect TF binding.

These predictions will then be validated using mutagenesis experiments. Results obtained will provide crucial insights into how TFs interpret the cis-regulatory code and how DNA mutations affect this interpretation. The Fellow will focus his outreach efforts on Native American high school students in Oklahoma by providing classroom career seminars, participation in an established tribal STEM fair, and the implementation of a yearly science fair.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.