# Molecular impediments to fate-specifying pioneer factor activity during development

> **NIH NIH R00** · WASHINGTON UNIVERSITY · 2024 · $248,589

## Abstract

Project Summary/Abstract
Transcription factors act as specifying agents of cell differentiation during development by binding to DNA
enhancer sequences and activating them to control developmental gene expression. Enhancer activation is
typically associated with the removal of nucleosomes, which decorate eukaryotic genomes and normally wrap
roughly 150 base pairs of DNA in a highly stable configuration. A persistent puzzle of developmental gene
regulation is how TFs bind and activate their target enhancers when they are initially wrapped in nucleosomes,
which typically inhibit TF binding. One hypothesis posits that a special class of “pioneer factors” are able to bind
their targets in the context of nucleosomal wrapping and displace the nucleosomes they bind to activate and
expose the enhancer for downstream TF binding. However, it has been exceedingly difficult to confirm the
presence of nucleosome binding “pioneer activity” in vivo, leaving the developmental roles of pioneer factors in
question. We recently used high-resolution epigenome profiling to identify instances of nucleosome binding by
pioneer factors that were enriched at enhancers with suboptimal motif binding sequences, presenting the
intriguing possibility that pioneer activity is a mechanism to ensure the fidelity of enhancer activation at sites that
are vulnerable to natural fluctuations in the local chromatin environment. Pioneer factors often function in early
development, which maintains high fidelity despite natural variation in chromatin structure that is sensitive to the
metabolic state of the cell. Therefore, pioneer factors may play a direct role in insulating developmental
transitions against metabolic variance. However, the potential roles of pioneer factors in developmental fidelity
and buffering against metabolic heterogeneity have not been uncovered to date. In this proposal, I will use a
controlled pioneer factor expression system to study how pioneer factor-driven developmental changes are
buffered against deliberate chromatin and metabolic perturbations. In Aim 1, I will test the hypothesis that pioneer
activity facilitates developmental fidelity by observing development after genetically enforcing chromatin barriers
to pioneer factor binding and inactivating the nucleosome binding pioneer activity of a specific pioneer factor. In
Aim 2, I will use a model system of metabolic control of development to understand how pioneer factor binding
responds to metabolic changes, and how specific pioneer factor-enhancer activation events underlie different
developmental outcomes in response. These Aims will uncover mechanistic explanations for the disparity
between variance in gene regulatory processes on the molecular level and the precision of cell fate outcomes
on the developmental level, and my findings will be of direct consequence to diseases such as cancer where
extreme heterogeneity overwhelms the checks and balances on cell fate. A K99/R00 Award will be instrumental
...

## Key facts

- **NIH application ID:** 10767366
- **Project number:** 5R00GM140251-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Michael P Meers
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $248,589
- **Award type:** 5
- **Project period:** 2021-03-03 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767366

## Citation

> US National Institutes of Health, RePORTER application 10767366, Molecular impediments to fate-specifying pioneer factor activity during development (5R00GM140251-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10767366. Licensed CC0.

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