# Mechanisms of Foxh1 pioneer factor action during mesendoderm development

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2020 · $397,200

## Abstract

Project Summary:
Cellular programs for development, once believed to be irreversible, are now known to be quite plastic. We
also know that the regulatory logic controlling developmental processes is hardwired in the genome. In other
words, developmentally controlled expression of confined gene sets determines the identity, cell fate and
function of fields of cells (subregions) within an embryo, from which various body parts develop with further
subdivisions of these territories. The essential control feature in the process of development is gene
regulation in time and space.
Access of transcription factors (TFs) to cis-regulatory modules (CRMs) is itself regulated by epigenetic
modifications on histone proteins, which modify nucleosome packing of DNA. TFs can also recruit histone-
modifying enzymes to CRMs to modify local nucleosome behavior in the vicinity of target genes to control
their accessibility and behavior. It is therefore important to understand the interplay between TFs and
epigenetic modifications. However, dissecting out these processes, in vivo, is challenging - In most cases
we need to deal with a complex tissue environment with numerous cell types, and cells at a given
differentiation state have already been subjected to epigenetic modifications by the time we examine the
process. Thus, it is difficult to clearly discern whether the specific binding of a TF is solely based on the
property of TF alone or the TF binding is restricted due to pre-existing epigenetic modifications. Fortunately,
we can address these fundamental questions by going back to the earliest stages of embryonic
development when transcription from the embryonic genome has not yet begun and the number of different
cell types is small.
Using Xenopus tropicalis (a true diploid), we found that the Foxh1 transcription factor, a well-known
mediator of Nodal/TGFβ in early mesendoderm development, plays key roles in coordinating transcription
initiated at the zygotic gene activation. When we examined Foxh1's dynamic action across early
development, we discovered that Foxh1 recognizes the CRMs of target genes during early cleavage stages,
before any signs of epigenetic histone marking, and marks these regions well in advance of zygotic gene
transcription. We hypothesize that Foxh1 is the maternal master-regulator that is upstream of key circuitry
regulating the mesendodermal hierarchy and regulates chromatin states so that these bookmarked genes
are selectively activated at appropriate developmental stages. Importantly, we also discovered that Foxh1
recruits the co-repressor Tle (Groucho) to cis-regulatory modules in the early blastula, and subsequently
coordinates the recruitment of a well known endodermal pioneer factor Foxa. Based on these observations,
we propose the following specific aims.
 Aim 1: How does Foxh1 interact dynamically with Tle and Foxa to regulate gene expression?
 Aim 2: What are the structural features of CRMs marked by Foxh1 that enable them to r...

## Key facts

- **NIH application ID:** 9934251
- **Project number:** 5R01GM126395-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Ken W.Y. Cho
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,200
- **Award type:** 5
- **Project period:** 2017-09-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934251

## Citation

> US National Institutes of Health, RePORTER application 9934251, Mechanisms of Foxh1 pioneer factor action during mesendoderm development (5R01GM126395-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9934251. Licensed CC0.

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