Pou5f3, SoxB1, and Nanog Remodel Chromatin on High Nucleosome Affinity Regions at Zygotic Genome Activation

The zebrafish embryo is transcriptionally mostly quiescent during the first 10 cell cycles, until the main wave of zygotic genome activation (ZGA) occurs, accompanied by fast chromatin remodeling. At ZGA, homologs of the mammalian stem cell transcription factors (TFs) Pou5f3, Nanog, and Sox19b bind to thousands of developmental enhancers to initiate transcription. So far, how these TFs influence chromatin dynamics at ZGA has remained unresolved. To address this question, we analyzed nucleosome positions in wild-type and maternal-zygotic (MZ) mutants for pou5f3 and nanog by MNase-seq. We show that Nanog, Sox19b, and Pou5f3 bind to the high nucleosome affinity regions (HNARs). HNARs are spanning over 600 bp, featuring high in vivo and predicted in vitro nucleosome occupancy and high predicted propeller twist DNA shape value. We suggest a two-step nucleosome destabilization-depletion model, in which the same intrinsic DNA properties of HNAR promote both high nucleosome occupancy and differential binding of TFs. In the first step, already before ZGA, Pou5f3 and Nanog destabilize nucleosomes at HNAR centers genome-wide. In the second step, post-ZGA, Nanog, Pou5f3, and SoxB1 maintain open chromatin state on the subset of HNARs, acting synergistically. Nanog binds to the HNAR center, whereas the Pou5f3 stabilizes the flanks. The HNAR model will provide a useful tool for genome regulatory studies in a variety of biological systems

Öffnung des Wohnquartiers für das Alter. Entwicklung einer kommunikativen Informationsinfrastruktur zur Überbrückung struktureller Löcher im Sozialraum

Im Blickpunkt stehen ältere Menschen, die in ihrer privaten Lebensführung zurückgezogen leben, wenig in lokale Beziehungsnetzwerke involviert sind und die von Informationen und Angeboten der Altenhilfeträger bisher nicht erreicht werden. Für diese Menschen wurde die Idee einer „kommunikativen Informationsinfrastruktur“ im Sozialraum des Wohnviertels und Stadtteils entwickelt. Mit dem Infrastrukturmodell soll vermieden werden, dass solche Personen unerkannt in Notsituationen geraten, aber auch sichergestellt werden, dass sie kontinuierlich über Gelegenheiten zur erfolgreichen Bewältigung ihrer Lebenssituation informiert werden. Das Buch beschreibt das entwickelte Modell und die Erfahrungen mit der praktischen Umsetzung. Das Modell zeigt Perspektiven für die Sozialplanung auf, dass zwischen privater Lebensführung im Alter und öffentlicher Daseinsvorsorge der Altenhilfe wirkungsvoll vermittelt werden kann. Zurückgezogen lebende ältere Menschen werden aus dem lokalen Umfeld unterstützt, sich umfassend zu informieren und Chancen zur Mitgestaltung von Angeboten gemäß ihren Bedürfnissen wahrzunehmen

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

Abstract 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

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 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