Trophectoderm (TE) lineage development is pivotal for proper implantation, placentation, and healthy pregnancy. However, only a few TE-specific transcription factors (TFs) have been systematically characterized, hindering our understanding of the process. To elucidate regulatory mechanisms underlying TE development, here we map super-enhancers (SEs) in trophoblast stem cells (TSCs) as a model. We find both prominent TE-specific master TFs (Cdx2, Gata3, and Tead4), and >150 TFs that had not been previously implicated in TE lineage, that are SE-associated. Mapping targets of 27 SE-predicted TFs reveals a highly intertwined transcriptional regulatory circuitry. Intriguingly, SE-predicted TFs show 4 distinct expression patterns with dynamic alterations of their targets during TSC differentiation. Furthermore, depletion of a subset of TFs results in dysregulation of the markers for specialized cell types in placenta, suggesting a role during TE differentiation. Collectively, we characterize an expanded TE-specific regulatory network, providing a framework for understanding TE lineage development and placentation.
Approximately, 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via cis-regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.
Conidial formation in the filamentous fungus Neurospora crassa is regulated by nutritional conditions, light, and the circadian clock. We found that a sod-1 mutant, with a defective superoxide dismutase catalyzing the conversion of superoxide to hydrogen peroxide, had a slightly shorter period length than the wild type and clear conidial banding similar to a mutant of band (bd). However, unlike the bd mutant, the sod-1 mutant could sustain conidial banding with light pulses on a nutrient-rich medium, which involved an enhancement of the light-induced transcription of frequency (frq). sod-1 was hypersensitive to entrainment of the conidiation rhythm by light in race tubes. Furthermore, a frq(10); sod-1 double mutant showed conidiation rhythm in darkness and could be synchronized to light/dark cycles by the masking effect of light. These genetic analyses suggested that intracellular reactive oxygen species (ROS) act on circadian conidiation via multiple circadian clocks and output pathways.
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