Foxh1 Occupies cis-Regulatory Modules Prior to Dynamic Transcription Factor Interactions Controlling the Mesendoderm Gene Program

Abstract

Summary The interplay between transcription factors and chromatin dictates gene regulatory network activity. Germ layer specification is tightly coupled with zygotic gene activation and, in most metazoans, is dependent upon maternal factors. We explore the dynamic genome-wide interactions of Foxh1, a maternal transcription factor that mediates Nodal/TGFβ signaling, with cis-regulatory modules (CRMs) during mesendodermal specification. Foxh1 marks CRMs during cleavage stages and recruits the co-repressor Tle/Groucho in the early blastula. We highlight a population of CRMs that are continuously occupied by Foxh1, and show they are marked by H3K4me1, Ep300, and Fox/Sox/Smad motifs, suggesting interplay between these factors in gene regulation. We also propose a molecular ‘hand-off’ between maternal Foxh1 and zygotic Foxa at these CRMs to maintain enhancer activation. Our findings suggest that Foxh1 functions at the top of a hierarchy of interactions by marking developmental genes for activation beginning with the onset of zygotic gene expression.

Chromatin accessibility and histone acetylation in the regulation of competence in early development

“…In Xenopus, for example, Wnt signaling directs the arginine methyltransferase PRMT2 to dorsal Wnt target genes prior to zygotic gene activation (ZGA), establishing a primed chromatin state at promoters that become active at later stages, once global zygotic gene expression has been activated (Blythe et al, 2010). Later in the blastula stage, maternal transcription factors including Fox, Sox, and Oct/Pou family members modify chromatin more globally to establish competence for primary germ layer formation (Charney et al, 2017;Gentsch et al, 2019;Paraiso et al, 2019). In a role analogous to maternal transcription factors Zelda and Grainyhead in Drosophila (Jacobs et al, 2018;McDaniel et al, 2019), maternal Sox and Oct/Pou family transcription factors are required for activation of zygotic gene expression in zebrafish and X. tropicalis (Gentsch et al, 2019;Lee et al, 2013;Leichsenring et al, 2013;Paraiso et al, 2019), functioning as pioneer factors that confer competence for inductive signals at the time of zygotic gene activation (Gentsch et al, 2019).…”

Identification of FOXH1 mutations in patients with sporadic conotruncal heart defect

“…Transcription factor dysfunction has recently been implicated in the pathogenesis of CTD . FOXH1 is a transcription factor with an important role in cardiac development . In particular, Foxh1 is expressed during the early embryonic stages and is purported to be involved in the normal formation of the cardiac OFT.…”

“…19,20 FOXH1 is a transcription factor with an important role in cardiac development. 21,22 In particular, Foxh1 is expressed during the early embryonic stages and is purported to be involved in the normal formation of the cardiac OFT. Less is known, however, about Foxh1 expression after E9.5 in mouse embryos.…”

Advancing genetic and genomic technologies deepen the pool for discovery in Xenopus tropicalis

“…In addition to these transcriptomic technologies, which are also quite tractable in X. laevis , the more streamlined genome of X. tropicalis is highly amenable to epigenomic interrogation by methods like ChIP‐Seq and ATAC‐Seq . Notably, the external development and large size of early Xenopus embryos has allowed several studies characterizing the temporal dynamics of early‐embryonic transcription factor occupancy, the histone code at promoters and enhancers, and the transition from maternal to zygotic transcription . Adding an additional layer to these characterizations of transcriptional regulation, the extremely large blastomeres of Xenopus provide the extraordinary opportunity to carry out not only proteomic profiling of early embryos but even of individual cells, an approach that has so far been applied in X. laevis but is likely to be tractable in X. tropicalis as well .…”

“…24 Notably, the external development and large size of early Xenopus embryos has allowed several studies characterizing the temporal dynamics of early-embryonic transcription factor occupancy, the histone code at promoters and enhancers, and the transition from maternal to zygotic transcription. [25][26][27][28][29] Adding an additional layer to these characterizations of transcriptional regulation, the extremely large blastomeres of Xenopus provide the extraordinary opportunity to carry out not only proteomic profiling of early embryos but even of individual cells, an approach that has so far been applied in X. laevis but is likely to be tractable in X. tropicalis as well. [30][31][32] Finally, genomic analysis is greatly facilitated by excellent support from the community web resource Xenbase, which has created a centralized pipeline for analysis and display of next-gen sequencing data and updates to genome assembly and annotation files 33 (http://www.xenbase.org/).…”