How the early embryonic genome ? through a progressive series of epigenetic modifications controls zygotic gene transcription, both in `time and space' ? to ensure proper cellular differentiation programs, is a major question in biology. Crucial to this process is the activity of a subset of transcription factors (TFs), which sit high in the regulatory hierarchy to control gene expression through combinatorial interactions with cis- regulatory modules (CRMs) that include enhancers, insulators and silencers. DNA sequence motifs present in the CRMs of genes act as a code to dictate which genes are to be utilized at the right time, and thus activate specific gene regulatory programs. ChIP-seq analysis of many TFs usually identifies tens of thousands of TF binding ?peaks,? genomewide, for a given cell type, but only a fraction of these sites appears to be functional. If so, what mechanistic constrains are needed to properly regulate gene expression? These questions are fundamentally important, but a difficult question to address in vivo using mammalian embryos due to the need for relatively large numbers of embryos for genome-scale analyses across numerous experimental regimens. Here we tackle this question by leveraging the strengths of the frog embryo system and examine the events of zygotic genome activation (ZGA). As the embryo transitions from fertilized egg to pluripotent zygotic cells giving rise to three germ layer cell fates, the embryonic genome and transcriptome need to be rapidly reprogrammed. How can maternal TFs collectively reprogram the genome during the ZGA remains an important area for the current research. Our recent work shows that a network of maternal TFs encoding Fox, Sox and Pou type proteins acts through conserved mechanisms to reprogram the cellular genome into the embryonic states. This is in part accomplished by forming enhanceososme complexes on the enhancers of target genes, resulting in changing in histone modifications surrounding genes, and forming super enhances, which concentrate the transcription apparatus and form phase-separated multimolecular assemblies in the nucleus. Our premise is that maternally expressed Foxh1 and its interacting partner TFs (Sox3 and Pou5f) function at the top of a hierarchy of TF interactions to not only mark developmental genes for activation prior to the onset of zygotic gene expression, but also coordinate major reorganization of the epigenetic landscape during ZGA. Through our efforts to elucidate these conserved developmental mechanisms controlling pluripotency, our goal is to uncover the integrative roles of maternal TFs in regulating the onset of ZGA, coordinating nucleosome phasing and histone modifications on target genes, and shaping the 3D architecture of chromatin. We combine both genomic and imaging approaches to provide important insights into the unifying principles that drive genome activation. 1

Public Health Relevance

A central question in biology is to understand how the naive genome in the early embryo progressively undergoes a series of modifications to control gene expression in ?time and space? such that proper cellular differentiation programs are correctly implemented. We recently investigated embryonic germ layer formation, the earliest cell fate determination process and demonstrated that Foxh1 and its associated transcription factors functions at the top of a hierarchy of interactions by marking developmental genes for activation beginning with the onset of zygotic gene expression. Here, we propose to tease out the interactions between maternal transcription factors and chromatin and uncover how the genome of embryos undergoes major structural changes as they proceed from pluripotent to differentiated cell states.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Hoodbhoy, Tanya
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University of California Irvine
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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