# Nuclear Pore Complexes As Scaffolds For Genome Architecture And Epigenetic Maintenance

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $338,100

## Abstract

Abstract:
The Nuclear Pore Complex (NPC) is a nuclear envelope-embedded multi-component complex,
which mediates transport of molecules between the nucleus and the cytoplasm. In addition to
their classical function in transport, NPC components (Nups) have been implicated in
transcriptional regulation via binding to the genome. Yet what regulatory steps of transcription
are controlled by Nups and how chromatin-binding roles of Nups contribute to metazoan
development is currently unclear. We identified the binding of multiple Nups to hundreds of
promoters and enhancers in the Drosophila genome, and discovered a previously unreported
role of the NPC in the formation of enhancer-promoter loops. Specifically, we identified Nup98
to be required for the formation of an enhancer-promoter loop at a gene activated by a
developmental hormone ecdysone. Functionally, we found that the loss of Nup98-mediated
enhancer-promoter loop affected the primed response to subsequent activation or
transcriptional memory. Interestingly, ecdysone-regulated genes stably associated with nuclear
pores before and after activation, suggesting that metazoan NPCs can be utilized as an
organizing scaffold for genes awaiting future activation events. Together, these findings
implicate Nups as a new class of architectural proteins for enhancers and suggest that
stabilization of enhancer-promoter loops by nuclear pore binding constitutes a mechanism of
epigenetic maintenance. We project that this function of the nuclear pore will be highly relevant
to gene regulation during metazoan development. To be able to investigate the genome-
organizing role of Nups in developmental gene regulation, we first plan to identify molecular
determinants of Nup-mediated enhancer-promoter looping. Thus, in Aim 1, we will define which
Nups and which other architectural proteins participate in the establishment of ecdysone-
induced genomic loops. Additionally, we plan to identify DNA elements that are sufficient to
tether to the NPC or that are necessary for loop stabilization. In Aim 2, we propose to define the
relationship between formation of Nup-mediated enhancer-promoter loops and transcriptional
activation and memory, by identifying chromatin changes that occur as a specific consequence
of looping. Furthermore, we will examine the effect of Nups on maintenance of genomic loops in
fly tissues during development and identify a comprehensive set of genomic contacts that are
regulated by Nups. Together, these experiments are expected to expand our knowledge of the
driving forces and principles of genome architecture, gene expression and nuclear pore biology.

## Key facts

- **NIH application ID:** 10249254
- **Project number:** 5R01GM124143-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Maya Capelson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $338,100
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249254

## Citation

> US National Institutes of Health, RePORTER application 10249254, Nuclear Pore Complexes As Scaffolds For Genome Architecture And Epigenetic Maintenance (5R01GM124143-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10249254. Licensed CC0.

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