The research project will contribute to our understanding of 3D genome folding. Proper regulation of gene expression is essential in all biological organisms. In mammals, most genes are regulated by distal enhancers that can be located far away from their target genes on the linear genome. Perhaps for this reason, mammalian genomes are folded into 3D domains that ensure enhancers interact with the appropriate genes through space. This research will provide key insights into an understudied potential regulator of 3D genome domains. The project will create interdisciplinary training opportunities for a graduate student and a post-doctoral associate, supporting their development as scientists in academia, biomedical industry and/or related careers. Additional broader impact will be achieved through integration of the imaging aspects of the project with an undergraduate course at MIT (20.309), summer research opportunities for undergraduates from underrepresented groups in STEM disciplines and through outreach activities.

CTCF is the best-known insulator between enhancers and promoters in mammalian cells. CTCF, together with the cohesin complex, fold the genome into chromatin loops and loop domains. However, not all loops have CTCF at their anchors, and since CTCF is expressed in all cell types, it is currently difficult to explain why loops differ between cell types. Moreover, several studies have provided evidence that other DNA-binding proteins are strongly enriched at loop anchors. The research will study such a candidate looping factor, ZNF143, in detail. Acute depletion followed by Micro-C will reveal its role in 3D genome organization and looping. Live-cell and super-resolution microscopy will reveal its dynamics, target-search mechanism, residence time, and provide quantitative constraints on 3D genome models. Taken together, the research will expand knowledge of critical genome organizing factors beyond CTCF.

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.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Manju Hingorani
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Massachusetts Institute of Technology
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