# Information Integration and Energy Expenditure in Eukaryotic Gene Regulation

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2020 · $445,763

## Abstract

PROJECT ABSTRACT
Gene regulation – how genes are turned on in the right place, at the right time and in the right
amount – is a problem central to most areas of biology and medicine. Our understanding of
gene regulation began with classical studies in bacteria, which introduced the idea that proteins
called “transcription factors” (TFs) determine which gene is turned on by binding to regulatory
DNA sequences and recruiting RNA polymerase (RNAP). The situation in eukaryotes, however,
is far more complicated. We focus in this proposal on two critical aspects of eukaryotic gene
regulation that are not addressed in the bacterial paradigm. First, eukaryotic DNA is packaged
into chromatin and accessibility to TF binding sites is dynamically re-organised by continuously
expending external sources of energy, such as ATP. Second, in eukaryotes multi-protein co-
regulators such as mediator and CREB-binding protein (CBP) intercede between TFs and
RNAP, serving as “integrators” of regulatory information. Pioneering studies from several
laboratories have identified many of the molecular components involved in this regulatory
complexity, however, the quantitative concepts used to reason about how eukaryotic gene
regulation are still largely based on the bacterial paradigm. This is an alarming discrepancy in
light of the central importance of gene regulation. In recent work, we used mathematical models
rooted in physics to show that this bacterial paradigm cannot account for experimentally
measured data in eukaryotes. We examined, in particular, the question of how sharply a gene is
turned on in response to a TF, an important property in many contexts. We introduced new
concepts for analyzing information integration by co-regulators and energy expenditure and
showed how these processes could explain the observed sharpness. In this proposal, we seek
to build upon this highly-productive, inter-disciplinary collaboration. We will integrate
mathematical theory with quantitative experiments in the well-studied model organism
Drosophila melanogaster to identify which molecular mechanisms of information integration and
energy expenditure are involved in regulating the developmental gene hunchback, whose sharp
expression is crucial for patterning the early fruitfly embryo. As in the classical bacterial studies,
we anticipate that a deep analysis of this particular gene will provide a new foundation on which
to understand in quantitative terms the regulation of other eukaryotic genes and thus, that this
study will have broad impact across biology and medicine.

## Key facts

- **NIH application ID:** 9899260
- **Project number:** 5R01GM122928-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Angela H DePace
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,763
- **Award type:** 5
- **Project period:** 2017-04-10 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899260

## Citation

> US National Institutes of Health, RePORTER application 9899260, Information Integration and Energy Expenditure in Eukaryotic Gene Regulation (5R01GM122928-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9899260. Licensed CC0.

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