Pioneering the developmental frontier.

The fertilized frog egg contains all the materials needed to initiate development of a new organism, including stored RNAs and proteins deposited during oogenesis, thus the earliest stages of development do not require transcription. The onset of transcription from the zygotic genome marks the first genetic switch activating the gene regulatory network that programs embryonic development. Zygotic genome activation occurs after an initial phase of transcriptional quiescence that continues until the midblastula stage, a period called the midblastula transition, which was first identified in Xenopus. Activation of transcription is programmed by maternally supplied factors and is regulated at multiple levels. A similar switch exists in most animals and is of great interest both to developmental biologists and to those interested in understanding nuclear reprogramming. Here we review in detail our knowledge on this major switch in transcription in Xenopus and place recent discoveries in the context of a decades old problem.

Control of zygotic genome activation in Xenopus.

The first activation of gene expression during development (zygotic genome activation, ZGA) is accompanied by massive changes in chromosome organization. The connection between these two processes remains unknown. Using Hi-C for zebrafish embryos, we found that chromosome folding starts by establishing “fountains”, novel elements of chromosome organization, emerging selectively at enhancers upon ZGA. Using polymer simulations, we demonstrate that fountains can emerge as sites of targeted cohesin loading and require two-sided, yet desynchronized, loop extrusion. Specific loss of fountains upon loss of pioneer transcription factors that drive ZGA reveals a causal connection between enhancer activity and fountain formation. Finally, we show that fountains emerge in early Medaka and Xenopus embryos; moreover, we found cohesin-dependent fountain pattern on enhancers of mouse embryonic stem cells. Taken together, fountains are the first enhancer-specific elements of chromosome organization; they constitute starting points of chromosome folding during early development, likely serving as sites of targeted cohesin loading.

Extrusion fountains are hallmarks of chromosome organization emerging upon zygotic genome activation

Zygotic genome activation (ZGA) initiates regionalized transcription responsible for the acquisition of distinct cellular identities. ZGA is dependent upon dynamic chromatin architecture sculpted by conserved DNA-binding proteins. However, whether the tissue-specific transcription is mechanistically linked with the onset of ZGA is unknown. Here, we have addressed the involvement of chromatin organizer SATB2 in orchestrating these processes during vertebrate embryogenesis. Integrative analysis of transcriptome, genome-wide occupancy and chromatin accessibility revealed contrasting molecular functions of maternal and zygotic pools of Satb2. Maternal Satb2 represses zygotic genes by influencing the interplay between the pluripotency factors. By contrast, zygotic Satb2 activates transcription of the same group of genes during neural crest development and organogenesis. Comparative analysis of maternal versus zygotic function of Satb2 underscores how these antithetical activities are temporally coordinated and functionally implemented. We discuss the evolutionary implications of the biphasic and bimodal regulation of landmark developmental transitions by a single determinant.

/pdf/satb2-acts-as-a-gatekeeper-for-major-developmental-1kb85xk28i.pdf

Satb2 acts as a gatekeeper for major developmental transitions during early vertebrate embryogenesis

Zygotic genome activation (ZGA) in the development of flies, fish, frogs and mammals depends on pioneer-like transcription factors (TFs). Those TFs create open chromatin regions, promote histone acetylation on enhancers, and activate transcription. Here, we use the panel of single, double and triple mutants for zebrafish genome activators Pou5f3, Sox19b and Nanog, multi-omics and mathematical modeling to investigate the combinatorial mechanisms of genome activation. We show that Pou5f3 and Nanog act differently on synergistic and antagonistic enhancer types. Pou5f3 and Nanog both bind as pioneer-like TFs on synergistic enhancers, promote histone acetylation and activate transcription. Antagonistic enhancers are activated by binding of one of these factors. The other TF binds as non-pioneer-like TF, competes with the activator and blocks all its effects, partially or completely. This activator-blocker mechanism mutually restricts widespread transcriptional activation by Pou5f3 and Nanog and prevents premature expression of late developmental regulators in the early embryo. 

pdf/activator-blocker-model-of-transcriptional-regulation-by-4p57n4l4gn.pdf

Activator-blocker model of transcriptional regulation by pioneer-like factors

Awakening of zygotic transcription in animal embryos relies on maternal pioneer transcription factors. The interplay of global and specific functions of these proteins remains poorly understood. Here, we analyze chromatin accessibility and time-resolved transcription in single and double mutant zebrafish embryos lacking pluripotency factors Pou5f3 and Sox19b. We show that two factors modify chromatin in a largely independent manner. We distinguish four types of direct enhancers by differential requirements for Pou5f3 or Sox19b. We demonstrate that changes in chromatin accessibility of enhancers underlie the changes in zygotic expression repertoire in the double mutants. Pou5f3 or Sox19b promote chromatin accessibility of enhancers linked to the genes involved in gastrulation and ventral fate specification. The genes regulating mesendodermal and dorsal fates are primed for activation independently of Pou5f3 and Sox19b. Strikingly, simultaneous loss of Pou5f3 and Sox19b leads to premature expression of genes, involved in regulation of organogenesis and differentiation. 

/pdf/pluripotency-factors-determine-gene-expression-repertoire-at-6y523ngn.pdf

Pluripotency factors determine gene expression repertoire at zygotic genome activation

Awakening of zygotic transcription in animal embryos relies on maternal pioneer transcription factors. The interplay of global and specific functions of these proteins remains poorly understood. Here, we analyzed nucleosome positioning, H3K27 acetylation, transcription, and gastrulation rates in zebrafish embryos lacking pluripotency factors Pou5f3 and Sox19b. We show that the bulk transcriptional onset does not require Sox19b and Pou5f3, but is sensitive to their balance. Pou5f3 docks H3K27ac on the enhancers of genes involved in gastrulation and ventral fate specification. Sox19b facilitates Pou5f3 access to one-third of these enhancers. The genes regulating mesendodermal and dorsal fates are primed for activation independently on Pou5f3 and Sox19b. Strikingly, the loss of either factor results in activation of silent enhancers; simultaneous loss of both leads to premature expression of differentiation genes. Our results uncover how independent activities of maternal Pou5f3 and Sox19b add up or antagonize to determine the early gene expression repertoire.

https://www.biorxiv.org/content/biorxiv/early/2020/05/06/2020.02.16.949362.full.pdf

Pou5f3 and Sox19b select gene expression repertoire at Zygotic Genome Activation

Zygotic genome activation (ZGA) in the development of flies, fish, frogs and mammals depends on pioneer-like transcription factors (TFs). Those TFs create open chromatin regions, promote histone acetylation on enhancers, and activate transcription. Here, we use the panel of single, double and triple mutants for zebrafish genome activators Pou5f3, Sox19b and Nanog, multi-omics and mathematical modeling to investigate the combinatorial mechanisms of genome activation. We show that Pou5f3 and Nanog act differently on synergistic and antagonistic enhancer types. Pou5f3 and Nanog both bind as pioneers on synergistic enhancers, promote histone acetylation and activate transcription. Antagonistic enhancers are activated by pioneer binding of one of these factors. The other TF binds as non-pioneer, competes with the activator and blocks all its effects, partially or completely. This activator-blocker mechanism mutually restricts widespread transcriptional activation by Pou5f3 and Nanog and prevents premature expression of late developmental regulators in the early embryo. Pou5f3 and Nanog compete as pioneer-like and non-pioneer factors on common genomic sites. Pioneer-like binding activates transcription, non-pioneer binding blocks transcription. Competition between Pou5f3 and Nanog establishes the order of gene expression.

/pdf/activator-blocker-model-of-transcriptional-regulation-by-sqymfipv.pdf

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Pluripotency factors determine gene expression repertoire at zygotic genome activation

Pou5f3 and Sox19b select gene expression repertoire at Zygotic Genome Activation

Activator-blocker model of transcriptional regulation by pioneer-like factors