Collaborative Research: Data-driven spatial genomics modeling of X-chromosome inactivation at multiple scales

New York University, New York NY

Investigators

Abstract

How DNA is organized into chromosomes in human cells and how this complex folding controls gene expression fundamental to life defines one of the Grand Challenges of biology. Because chromosome folding occurs over a wide range of length and times scales, a sophisticated combination of experimental and computational approaches is required to unravel genome organization. In this collaborative project, a team from NYU (Tamar Schlick), Harvard (Anna Lappala and Jeannie Lee), and New Mexico Consortium (Karissa Sanbonmatsu) will combine expertise in molecular biology, genomics, computational biology, biophysics and biomolecular modeling in an integrated experimental and computational effort to address key mechanistic questions about X-chromosome structure and function. Inactivation influences X chromosome expression in females and has profound health implications. A better understanding of X-chromosome folding and gene expression will lead to new avenues for treating other diseases related to X-chromosome status. The research program will offer interdisciplinary and multidisciplinary training to young scientists in STEM fields, through hands on mentoring and participation in summer camps, promoting national needs in education and innovation in Science and Engineering. Public outreach will be further enhanced by communicating these scientific and societal advances in the form of a public museum exhibit. Advances in epigenomic methods have opened new avenues in chromosome folding studies. Yet translating such experimental information into three-dimensional gene structures is complex. The team will focus on X-chromosome inactivation (XCI), a balancing of X-linked gene expression between females and males, and will dissect this process at multiple scales – from nucleosomes to chromosomes. The team will integrate high-resolution genomics data with advanced spatial modeling to unravel XCI dynamics to interpret related gene function and activity. Namely, Lappala’s gene modeling techniques, Lee’s structure / function studies of the X-chromosome, Sanbonmatsu's chromosome dynamics simulations on the macroscale, and Schlick’s gene and chromatin modeling and simulations at the mesoscale will shed light on genome organization and function. Included are delineation of protein-mediated effects by cohesin and CTCF complexes on XCI and development of models of XCI at various spatial and temporal resolutions. The research will deepen our understanding of XCI and related mechanisms of chromatin organization and epigenetic regulation, offering new modeling and simulation tools for genes and chromosomes and advancing the fields of genomics and epigenetics. This project is jointly funded by the Molecular Biophysics Program in the Molecular and Cellular Biosciences Division of the Biological Sciences Directorate and the Established Program to Stimulate Competitive Research (EPSCoR). 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.