# Predictive understanding of the temporal control of transcription in Drosophila development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2021 · $301,962

## Abstract

Project Summary/Abstract
The correct implementation of developmental programs depends on information encoded in an organism's
DNA. Despite decades of work in dissecting the spatial control of gene expression in embryonic development,
we know relatively little about the temporal control of these programs—largely due to reliance on dead, fixed
tissues. Recently, our lab established new technologies for real-time measurements of input transcription factor
concentration dynamics and output transcriptional activity in single cells of the early embryo of the fruit fly
Drosophila melanogaster. Our measurements have revealed that the timing of transcription in development is
under precise control.
Here, we propose a dialogue between theory and experiment to dissect this largely unexplored layer of
transcriptional control using the regulation of the hunchback gene by the activator Bicoid and the pioneer-like
transcription factor Zelda as a case study. Recent work from our lab has suggested that hunchback
transcription ensues as a result of the transition of its promoter through multiple transcriptionally silent states.
In this model, Bicoid and Zelda catalyze the transitions between silent states, presumably by triggering the
acetylation of nearby histones. In order to systematically test this model of transcriptional onset and reveal the
molecular identities of the pathways involved in the dictating transcriptional onset, we will (i) exploit
optogenetics to determine whether the timing Bicoid- and Zelda-driven transcriptional onset is independent of
the control of mRNA production rates once transcription has already ensued, (ii) harness measurements of the
distribution of transcriptional onset times in single cells to uncover the structure of the biochemical cascade
leading to transcriptional onset and how this cascade is modulated by Bicoid and Zelda binding, and (iii)
identify the histone acetylases and deacetylases invoked by Bicoid and Zelda to dictate transcriptional onset, a
process that takes place at time scales that are not accessible by commonplace genome-wide approaches to
dissect the chromatin landscape.
Overall, our proposed work will establish a clear workflow for the dissection of this new layer of regulatory
control given by the timing of transcription in development and for uncovering the underlying molecular
pathways. This approach will be amenable to be implemented in other relevant genes in the fruit fly as well as
in other workhorses of developmental biology. Further, we envision that our quantitative and predictive
approach to dissecting developmental programs will empower future synthetic applications as well as
reengineering of multicellular organisms, for example to fix developmental defects or to halt states of
unchecked cellular proliferation.

## Key facts

- **NIH application ID:** 10096817
- **Project number:** 1R01GM139913-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Hernan Gustavo Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $301,962
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10096817

## Citation

> US National Institutes of Health, RePORTER application 10096817, Predictive understanding of the temporal control of transcription in Drosophila development (1R01GM139913-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10096817. Licensed CC0.

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