Enhancer-promoter communication in Drosophila developmental gene transcription.

Enhancers play an essential role in gene regulation by receiving cues from transcription factors and relaying these signals to modulate transcription from target promoters. Enhancer-promoter communications occur across large linear distances of the genome and with high specificity. The molecular mechanisms that underlie enhancer-mediated control of transcription remain unresolved. In this review, we focus on research in Drosophila uncovering the molecular mechanisms governing enhancer-promoter communication and discuss the current understanding of developmental gene regulation. The functions of protein acetylation, pausing of RNA polymerase II, transcriptional bursting, and the formation of nuclear hubs in the induction of tissue-specific programs of transcription during zygotic genome activation are considered.

Tissue-specific RNA Polymerase II promoter-proximal pause release and burst kinetics in a Drosophila embryonic patterning network.

BACKGROUND: Formation of tissue-specific transcriptional programs underlies multicellular development, including dorsoventral (DV) patterning of the Drosophila embryo. This involves interactions between transcriptional enhancers and promoters in a chromatin context, but how the chromatin landscape influences transcription is not fully understood. RESULTS: Here we comprehensively resolve differential transcriptional and chromatin states during Drosophila DV patterning. We find that RNA Polymerase II pausing is established at DV promoters prior to zygotic genome activation (ZGA), that pausing persists irrespective of cell fate, but that release into productive elongation is tightly regulated and accompanied by tissue-specific P-TEFb recruitment. DV enhancers acquire distinct tissue-specific chromatin states through CBP-mediated histone acetylation that predict the transcriptional output of target genes, whereas promoter states are more tissue-invariant. Transcriptome-wide inference of burst kinetics in different cell types revealed that while DV genes are generally characterized by a high burst size, either burst size or frequency can differ between tissues. CONCLUSIONS: The data suggest that pausing is established by pioneer transcription factors prior to ZGA and that release from pausing is imparted by enhancer chromatin state to regulate bursting in a tissue-specific manner in the early embryo. Our results uncover how developmental patterning is orchestrated by tissue-specific bursts of transcription from Pol II primed promoters in response to enhancer regulatory cues.

p300/CBP sustains Polycomb silencing by non-enzymatic functions.

Maintenance of appropriate cell states involves epigenetic mechanisms, including Polycomb-group (PcG)-mediated transcriptional repression. While PcG proteins are known to induce chromatin compaction, how PcG proteins gain access to DNA in compact chromatin to achieve long-term silencing is poorly understood. Here, we show that the p300/CREB-binding protein (CBP) co-activator is associated with two-thirds of PcG regions and required for PcG occupancy at many of these in Drosophila and mouse cells. CBP stabilizes RNA polymerase II (Pol II) at PcG-bound repressive sites and promotes Pol II pausing independently of its histone acetyltransferase activity. CBP and Pol II pausing are necessary for RNA-DNA hybrid (R-loop) formation and nucleosome depletion at Polycomb Response Elements (PREs), whereas transcription beyond the pause region is not. These results suggest that non-enzymatic activities of the CBP co-activator have been repurposed to support PcG-mediated silencing, revealing how chromatin regulator interplay maintains transcriptional states.

The control of transcriptional memory by stable mitotic bookmarking.

To maintain cellular identities during development, gene expression profiles must be faithfully propagated through cell generations. The reestablishment of gene expression patterns upon mitotic exit is mediated, in part, by transcription factors (TF) mitotic bookmarking. However, the mechanisms and functions of TF mitotic bookmarking during early embryogenesis remain poorly understood. In this study, taking advantage of the naturally synchronized mitoses of Drosophila early embryos, we provide evidence that GAGA pioneer factor (GAF) acts as a stable mitotic bookmarker during zygotic genome activation. We show that, during mitosis, GAF remains associated to a large fraction of its interphase targets, including at cis-regulatory sequences of key developmental genes with both active and repressive chromatin signatures. GAF mitotic targets are globally accessible during mitosis and are bookmarked via histone acetylation (H4K8ac). By monitoring the kinetics of transcriptional activation in living embryos, we report that GAF binding establishes competence for rapid activation upon mitotic exit.

'Too male, too pale, too stale': a qualitative exploration of student experiences of gender bias within medical education.

OBJECTIVE: To explore medical student perceptions and experiences of gender bias within medical education. SETTING: Gender bias-'prejudiced actions or thoughts based on the perception that women are not equal to men'-is a widespread issue. Within medicine, the pay gap, under-representation of women in senior roles and sexual harassment are among the most concerning issues demonstrating its presence and impact. While research investigating experiences of clinicians is gaining traction, investigation of medical students' experiences is lacking. This qualitative study analyses medical students' experiences of gender bias within their education to discern any patterns to this bias. Illuminating the current state of medical education gender bias will hopefully highlight areas in which student experience could be improved. Constructivist thematic analysis was used to analyse data, informed by William's patterns of gender bias, intersectional feminism and communities of practice theory. PARTICIPANTS: Thirty-two medical students from multiple UK medical schools participated in individual interviews. Nine faculty members were also interviewed to triangulate data. RESULTS: Gender bias has an overt presence during medical student education, manifesting in line with William's patterns of bias, impacting career aspirations. Physical environments serve to manifest organisational values, sending implicit messages regarding who is most welcome-currently, this imagery remains 'too male, too pale…too stale'. Existing gender initiatives require careful scrutiny, as this work identifies the superficial application of positive action, and a failure to affect meaningful change. CONCLUSIONS: Despite progress having been made regarding overt gender discrimination, implicit bias persists, with existing positive action inadequate in promoting the advancement of women. Institutions should mandate participation in implicit bias education programmes for all staff and must strive to revise the imagery within physical environments to better represent society. Gender initiatives, like Athena Scientific Women's Academic Network, also require large-scale evaluation regarding their impact, which this work found to be lacking.

Timing of ice retreat alters seabird abundances and distributions in the southeast Bering Sea.

Timing of spring sea-ice retreat shapes the southeast Bering Sea food web. We compared summer seabird densities and average bathymetry depth distributions between years with early (typically warm) and late (typically cold) ice retreat. Averaged over all seabird species, densities in early-ice-retreat-years were 10.1% (95% CI: 1.1-47.9%) of that in late-ice-retreat-years. In early-ice-retreat-years, surface-foraging species had increased numbers over the middle shelf (50-150 m) and reduced numbers over the shelf slope (200-500 m). Pursuit-diving seabirds showed a less clear trend. Euphausiids and the copepod Calanus marshallae/glacialis were 2.4 and 18.1 times less abundant in early-ice-retreat-years, respectively, whereas age-0 walleye pollock Gadus chalcogrammus near-surface densities were 51× higher in early-ice-retreat-years. Our results suggest a mechanistic understanding of how present and future changes in sea-ice-retreat timing may affect top predators like seabirds in the southeastern Bering Sea.

Predictive modelling of habitat selection by marine predators with respect to the abundance and depth distribution of pelagic prey.

Understanding the ecological processes that underpin species distribution patterns is a fundamental goal in spatial ecology. However, developing predictive models of habitat use is challenging for species that forage in marine environments, as both predators and prey are often highly mobile and difficult to monitor. Consequently, few studies have developed resource selection functions for marine predators based directly on the abundance and distribution of their prey. We analysed contemporaneous data on the diving locations of two seabird species, the shallow-diving Peruvian Booby (Sula variegata) and deeper diving Guanay Cormorant (Phalacrocorax bougainvilliorum), and the abundance and depth distribution of their main prey, Peruvian anchoveta (Engraulis ringens). Based on this unique data set, we developed resource selection functions to test the hypothesis that the probability of seabird diving behaviour at a given location is a function of the relative abundance of prey in the upper water column. For both species, we show that the probability of diving behaviour is mostly explained by the distribution of prey at shallow depths. While the probability of diving behaviour increases sharply with prey abundance at relatively low levels of abundance, support for including abundance in addition to the depth distribution of prey is weak, suggesting that prey abundance was not a major factor determining the location of diving behaviour during the study period. The study thus highlights the importance of the depth distribution of prey for two species of seabird with different diving capabilities. The results complement previous research that points towards the importance of oceanographic processes that enhance the accessibility of prey to seabirds. The implications are that locations where prey is predictably found at accessible depths may be more important for surface foragers, such as seabirds, than locations where prey is predictably abundant. Analysis of the relative importance of abundance and accessibility is essential for the design and evaluation of effective management responses to reduced prey availability for seabirds and other top predators in marine systems.

Persistence of pharmaceuticals in effluent-dominated surface waters.

Pharmaceutical fate in surface water depends on a combination of physical and chemical processes, but currently, little information is available on cumulative dissipation rates in effluent-dominated receiving waters. In this study, dissipation rates were calculated for pharmaceutical compounds in two streams receiving municipal wastewater effluents using results from passive samplers. Seventeen pharmaceuticals were detected at the two sampling locations, and first-order dissipation rates were found to range between 0.03 and -0.02 h, indicating that some compounds were conserved, while others rapidly dissipated over several kilometers downstream of the source.