# Genetic and epigenetic mechanisms of developmental gene regulation

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $382,542

## Abstract

Project Summary/Abstract
 My lab is broadly focused on developmental gene regulation. We study the transcriptional mechanisms that
control determination and maintenance of cell fates over time. In particular, we seek to understand how access
to regulatory DNA is spatiotemporally controlled. Because many developmental disorders and diseases acquired
later in life are a consequence of gene regulatory defects, a better understanding of the underlying mechanisms
is crucial for preventing diseases and improving their outcomes. We combine genomic, genetic and biochemical
approaches in Drosophila melanogaster. The fly system offers multiple strengths, including a powerful ability to
manipulate gene activity with temporal and spatial precision, small genome size, which affords cheap genomics,
and a deep knowledge of the relevant genetic pathways, nearly all of which are conserved in humans.
 Research during the term of this grant will explore multiple questions at the core of modern developmental
biology and the field of epigenetic gene regulation. We will investigate how the transcriptional programs
underlying tissue identity are deployed in the proper temporal sequence during development. We have
uncovered a temporal cascade of transcription factors which we hypothesize control the sequential activation
and inactivation of transcriptional enhancers over time. We have termed these transcription factors as “chromatin
gatekeepers” due to their requirement for opening and closing access to DNA regulatory elements. The
mechanisms by which enhancers are inactivated, or “decommissioned” over time are particularly understudied.
One of our objectives is to decipher these mechanisms. We will also investigate how information about decisions
made earlier in development is propagated over time. A key to unlocking this question is a unique genetic
resource we recently generated that enables us to directly test the function of histones. Histones are subject to
a diverse array of post-translational modifications (PTMs) that are thought to serve as carriers of epigenetic
information to regulate many DNA-templated processes. However, evidence supporting a functional role of
histone PTMs in animals is largely correlative due to the difficulty in creating mutant histone genotypes in
animals. Drosophila is distinct amongst animal models in that the histone genes reside at a single locus in the
genome. We can replace the endogenous histone genes with tailor-made versions, thereby providing us with
the first opportunity to distinguish between regulatory information that is directly encoded in the DNA sequence,
and information that is epigenetically propagated. We will employ this approach to interrogate the molecular role
that histone PTMs play in enhancer regulation and in heritable control of gene expression. MIRA funding would
unify our research topics into a single funding mechanism. This will enable me to spend more time at the bench
mentoring students, collaborating wi...

## Key facts

- **NIH application ID:** 9973187
- **Project number:** 5R35GM128851-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Daniel J McKay
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,542
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973187

## Citation

> US National Institutes of Health, RePORTER application 9973187, Genetic and epigenetic mechanisms of developmental gene regulation (5R35GM128851-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973187. Licensed CC0.

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