# Mechanisms of shadow enhancer robustness during development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $302,331

## Abstract

Project Summary
Animal development is remarkably robust to many kinds of perturbations. Animals are able to
successfully develop into healthy adults despite the large amount of genetic variation in the population
and the environmental and intrinsic fluctuations to which the embryo is exposed during development.
However, development is not infinitely robust, and even small changes, e.g. a SNP in a developmental
enhancer, can lead to developmental defects. My long-term research goal is to elucidate how
some changes to the regulatory DNA that encodes the developmental program are tolerated,
while others have dramatic phenotypic effects.
 This proposal describes work to identify the mechanisms by which shadow enhancers provide
developmental systems the capability to withstand perturbations. Shadow enhancers are sets of
seemingly redundant enhancers that control a single gene and drive the same spatio-temporal
expression pattern. Developmental genes controlled by sets of shadow enhancers can better withstand
perturbations than genes controlled by a single enhancer. Shadow enhancers are a pervasive feature
of development and have been found in insects, mammals, and plants. A survey of ~1000
developmental genes in Drosophila found that nearly two-thirds of examined loci contained a set of
shadow enhancers. Despite their importance, there is no proven mechanism for how shadow
enhancers buffer perturbations to drive robust gene expression patterns. Dissecting these mechanisms
of robustness will allow us to predict what types of perturbations developmental systems can
successfully buffer and what types are intolerable, and to rationalize why certain steps in development
may be more fragile than others.
 To identify the mechanisms of shadow enhancer robustness, this proposal describes a
combination of quantitative experimental measurements and mathematical modeling of shadow
enhancer function under normal conditions and perturbation. The results of this work will distinguish
between two hypotheses that explain how shadow enhancers drive robust patterns of gene expression
in the face of both the inevitable noise that arises from discrete molecular processes and external
perturbations to the system. Success in these projects will also yield insight into how specific features
of shadow enhancers may be tuned to buffer specific types and amplitudes of perturbations during the
developmental process. Given the prevalence of shadow enhancers in controlling developmental
processes like neural crest specification and thymocyte development, understanding their mechanisms
of action may give insights in to why some developmental systems are more fragile than others and
may guide efforts to find causative mutations for developmental defects in non-coding DNA.

## Key facts

- **NIH application ID:** 9920735
- **Project number:** 5R01HD095246-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Zeba B Wunderlich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $302,331
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9920735

## Citation

> US National Institutes of Health, RePORTER application 9920735, Mechanisms of shadow enhancer robustness during development (5R01HD095246-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9920735. Licensed CC0.

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