# Investigating the molecular mechanisms of transcriptional regulation at Drosophila homeotic genes

> **NIH NIH R15** · CLARK UNIVERSITY (WORCESTER, MA) · 2020 · $450,900

## Abstract

Summary
The regulation of gene expression during embryonic development in Drosophila melanogaster, as in most other
organisms, is highly dependent on the activity of cis-regulatory modules (CRMs) in the genome. Transcription factor
(TF) proteins bind to such sequences, regulating expression of target genes by either activating or repressing
transcription. A critical question in modern developmental biology is how the architecture of multiple functional
TF binding sites is organized in CRMs to control the regulatory output. TFs frequently bind many sites within the
genome with varying affinity and are capable of complex protein-protein interactions. The goal of this project is
use integrated interdisciplinary, systems-level experimental, computational, bioinformatic and mathematical
approaches to investigate the regulatory logic that controls the activity of TF binding and interactions at CRMs and
the impact on gene expression in early Drosophila development. The results will inform our fundamental
understanding of key transcriptional regulatory mechanisms during embryonic development.
In the early Drosophila embryo, CRMs, under the control of TF concentration gradients, direct the spatio-temporal
expression of a network of developmental genes, including the highly conserved homeotic genes in the bithorax
complex (BX-C). The homeotic genes are critical for differentiation and specification of many important structures
in development. Preliminary studies from the PIs’ labs show that CRM sequences in the BX-C are rapidly evolving in
Drosophila species. Despite the general lack of conservation, these experiments discovered the preservation of an
organized spatial arrangement of critical TF binding sites, representing signature motifs, within a number of CRMs.
The ability to utilize integrated experimental approaches provides an exciting opportunity to expand the scope of
the functional analysis of these signature motifs in CRMs.
The ultimate goal of this proposal is to elucidate the molecular mechanisms that control functional activity of
homeotic gene CRMs at the sequence level. The long term scientific goal of the PIs is to fully investigate the
mechanisms by which genomic regulatory regions achieve coordinated control of gene expression in the early
developmental networks in Drosophila. The major focus of this proposal will be to apply a systems-level approach
to decipher the precise molecular control of TF binding and interactions within CRMs in the BX-C of Drosophila
melanogaster. The discoveries from preliminary studies will be used as a foundation to specifically address the
molecular contribution of individual TF binding sites within known CRMs, investigate their combinatorial
interactions, and analyze their in vivo activity in two complementary Aims that incorporate both experimental and
computational approaches. Specifically, the proposed studies will address the mechanisms at play in the CRMs,
including the functional role of binding site ...

## Key facts

- **NIH application ID:** 9965464
- **Project number:** 1R15GM137250-01
- **Recipient organization:** CLARK UNIVERSITY (WORCESTER, MA)
- **Principal Investigator:** ROBERT A DREWELL
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,900
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9965464

## Citation

> US National Institutes of Health, RePORTER application 9965464, Investigating the molecular mechanisms of transcriptional regulation at Drosophila homeotic genes (1R15GM137250-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9965464. Licensed CC0.

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