Fate-determining transcription factors (TFs) can promote lineage-restricted transcriptional programs from common progenitor states. The inner cell mass (ICM) of mouse blastocysts co-expresses the TFs NANOG and GATA6, which drive the bifurcation of the ICM into either the epiblast (Epi) or the primitive endoderm (PrE), respectively. Here, we induce GATA6 in embryonic stem cells–that also express NANOG–to characterize how a state of co-expression of opposing TFs resolves into divergent lineages. Surprisingly, we find that GATA6 and NANOG co-bind at the vast majority of Epi and PrE enhancers, a phenomenon we also observe in blastocysts. The co-bound state is followed by eviction and repression of Epi TFs, and quick remodeling of chromatin and enhancer-promoter contacts thus establishing the PrE lineage while repressing the Epi fate. We propose that co-binding of GATA6 and NANOG at shared enhancers maintains ICM plasticity and promotes the rapid establishment of Epi- and PrE-specific transcriptional programs.
Establishment of divergent cell types from a common progenitor requires transcription factors (TFs) to promote lineage-restricted transcriptional programs while suppressing alternative fates. In the mouse blastocyst, cells of the inner cell mass (ICM) coexpress NANOG and GATA6, two TFs that drive the bifurcation of these progenitors into either the epiblast (Epi) or the primitive endoderm (PrE), respectively. Here, using in vitro differentiation, we describe the molecular mechanisms of how GATA6 quickly induces the PrE fate while repressing the Epi lineage. GATA6 functions as a pioneer TF by inducing nucleosome repositioning at regulatory elements controlling PrE genes, making them accessible for deposition of active histone marks and leading to rewiring of chromatin interactions and ultimately transcriptional activation. GATA6 also binds most regulatory elements of Epi genes followed by eviction of the Epi-specific TFs NANOG and SOX2, loss of active histone marks, and reduction in chromatin accessibility that culminates in transcriptional repression. Unexpectedly, evicted NANOG and SOX2 transiently bind PrE regulatory elements occupied by GATA6. Our study shows that GATA6 binds and modulate the same regulatory elements as Epi TFs, a phenomenon we also validated in blastocysts. We propose that the ability of PrE and Epi-specific TFs to extensively bind and regulate the same gene networks contributes to ICM plasticity and allows rapid cell lineage specification by coordinating both activation and repression of divergent transcriptional programs.
Nitrogen is a limiting nutrient for photosynthetic productivity. Yet biological nitrogen fixation which transforms abundant atmospheric nitrogen to bioavailable ammonia is largely restricted to bacteria. Epithemia spp. diatoms contain obligate, nitrogen-fixing endosymbionts, or 'diazoplasts', derived from cyanobacteria. They represent rare photosynthetic eukaryotes that have successfully coupled oxygenic photosynthesis with oxygen-sensitive nitrogenase activity. Here, we report a newly-isolated species, E. clementina, as a model to investigate endosymbiotic acquisition of this critical biological function. To detect the metabolic changes associated with endosymbiotic specialization, we compared nitrogen fixation, nitrogen utilization, and their regulatory pathways in the Epithemia diazoplast with its close free-living cyanobacteria relative, Crocosphaera subtropica. Unlike C. subtropica, we show that nitrogenase activity in the diazoplast is concurrent with, and even dependent on, host photosynthesis. In contrast to its expanded nitrogen-fixing activity, the diazoplast has diminished ability to utilize alternative nitrogen sources. Finally, while key regulators of nitrogen metabolism are retained in the diazoplast genome, we observed a conserved negative feedback regulation of nitrogen fixation to ammonium, but paradoxical nitrogen assimilation responses in the diazoplast compared with C. subtropica. Our results suggest key adaptations that facilitated the transition from free-living to endosymbiotic specialist diazotroph, including import of host carbohydrates, streamlined carbon catabolism favoring high respiratory rates, and altered nitrogen regulation to favor nitrogen transfer to the host. Elucidating how photosynthesis and nitrogen fixation are coupled in a eukaryotic cell has important implications for bioengineering nitrogen-fixing crop plants for sustainable agriculture.
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