MYB: A Key Transcription Factor in the Hematopoietic System Subject to Many Levels of Control.

MYB is a master regulator and pioneer factor highly expressed in hematopoietic progenitor cells (HPCs) where it contributes to the reprogramming processes operating during hematopoietic development. MYB plays a complex role being involved in several lineages of the hematopoietic system. At the molecular level, the MYB gene is subject to intricate regulation at many levels through several enhancer and promoter elements, through transcriptional elongation control, as well as post-transcriptional regulation. The protein is modulated by post-translational modifications (PTMs) such as SUMOylation restricting the expression of its downstream targets. Together with a range of interaction partners, cooperating transcription factors (TFs) and epigenetic regulators, MYB orchestrates a fine-tuned symphony of genes expressed during various stages of haematopoiesis. At the same time, the complex MYB system is vulnerable, being a target for unbalanced control and cancer development.

Systematic dissection of sequence features affecting binding specificity of a pioneer factor reveals binding synergy between FOXA1 and AP-1.

Despite the unique ability of pioneer factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called chromatin immunoprecipitation with integrated synthetic oligonucleotides (ChIP-ISO) to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1, in human A549 cells. Combining ChIP-ISO with in vitro and neural network analyses, we find that (1) FOXA1 binding is strongly affected by co-binding transcription factors (TFs) AP-1 and CEBPB; (2) FOXA1 and AP-1 show binding cooperativity in vitro; (3) FOXA1's binding is determined more by local sequences than chromatin context, including eu-/heterochromatin; and (4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.

Exploring the reciprocity between pioneer factors and development.

Development is regulated by coordinated changes in gene expression. Control of these changes in expression is largely governed by the binding of transcription factors to specific regulatory elements. However, the packaging of DNA into chromatin prevents the binding of many transcription factors. Pioneer factors overcome this barrier owing to unique properties that enable them to bind closed chromatin, promote accessibility and, in so doing, mediate binding of additional factors that activate gene expression. Because of these properties, pioneer factors act at the top of gene-regulatory networks and drive developmental transitions. Despite the ability to bind target motifs in closed chromatin, pioneer factors have cell type-specific chromatin occupancy and activity. Thus, developmental context clearly shapes pioneer-factor function. Here, we discuss this reciprocal interplay between pioneer factors and development: how pioneer factors control changes in cell fate and how cellular environment influences pioneer-factor binding and activity.

Pioneer Transcription Factors: The First Domino in Zygotic Genome Activation.

Zygotic genome activation (ZGA) is a pivotal event in mammalian embryogenesis, marking the transition from maternal to zygotic control of development. During the ZGA process that is characterized by the intricate cascade of gene expression, who tipped the first domino in a meticulously arranged sequence is a subject of paramount interest. Recently, Dux, Obox and Nr5a2 were identified as pioneer transcription factors that reside at the top of transcriptional hierarchy. Through co-option of retrotransposon elements as hubs for transcriptional activation, these pioneer transcription factors rewire the gene regulatory network, thus initiating ZGA. In this review, we provide a snapshot of the mechanisms underlying the functions of these pioneer transcription factors. We propose that ZGA is the starting point where the embryo's own genome begins to influence development trajectory, therefore in-depth dissecting the functions of pioneer transcription factors during ZGA will form a cornerstone of our understanding for early embryonic development, which will pave the way for advancing our grasp of mammalian developmental biology and optimizing in vitro production (IVP) techniques.

Estimation of spreading speeds and travelling waves for the lattice pioneer-climax competition system.

This paper concerns the invasion dynamics of the lattice pioneer-climax competition model with parameter regions in which the system is non-monotone. We estimate the spreading speeds and establish appropriate conditions under which the spreading speeds are linearly selected. Moreover, the existence of travelling waves is determined by constructing suitable upper and lower solutions. It shows that the spreading speed coincides with the minimum wave speed of travelling waves if the diffusion rate of the invasive species is larger or equal to that of the native species. Our results are new to estimate the spreading speed of non-monotone lattice pioneer-climax systems, and the techniques developed in this work can be used to study the invasion dynamics of the pioneer-climax system with interaction delays, which could extend the results in the literature. The analysis replies on the construction of auxiliary systems, upper and lower solutions, and the monotone dynamical system approach.

Population differentiation and dynamics of five pioneer species of Gaultheria from the secondary forests in subtropical China.

BACKGROUND: The influence of native secondary succession associated with anthropogenic disturbance on the biodiversity of the forests in subtropical China remains uncertain. In particular, the evolutionary response of small understory shrubs, particularly pioneer species inhabiting continuously disturbed habitats, to topographic heterogeneity and climate change is poorly understood. This study aimed to address this knowledge gap by focusing on the Gaultheria crenulata group, a clade of small pioneer shrubs in subtropical China. RESULTS: We examined the genetic structure and demographic history of all five species of the G. crenulata group with two maternally inherited chloroplast DNA (cpDNA) fragments and two biparentally inherited low-copy nuclear genes (LCG) over 89 natural populations. We found that the genetic differentiation of this group was influenced by the geomorphological boundary between different regions of China in association with Quaternary climatic events. Despite low overall genetic diversity, we observed an isolation-by-distance (IBD) pattern at a regional scale, rather than isolation-by-environment (IBE), which was attributed to ongoing human disturbance in the region. CONCLUSION: Our findings suggest that the genetic structure of the G. crenulata group reflects the interplay of geological topography, historical climates, and anthropogenic disturbance during the Pliocene-Pleistocene-Holocene periods in subtropical China. The observed IBD pattern, particularly prominent in western China, highlights the role of limited dispersal and gene flow, possibly influenced by physical barriers or decreased connectivity over geographic distance. Furthermore, the east-to-west trend of gene flow, potentially facilitated by the East Asian monsoon system, underscores the complex interplay of biotic and abiotic factors shaping the genetic dynamics of pioneer species in subtropical China's secondary forests. These findings can be used to assess the impact of environmental changes on the adaptation and persistence of biodiversity in subtropical forest ecosystems.

Friedrich Dessauer (1881-1963): the forgotten medical physicist, politician, and philosopher.

Today, the name Friedrich Dessauer is almost forgotten; however, his scientific, social, and political works should not be. Dessauer's professional career began at a young age as a professor of physics in Frankfurt am Main. It is said that he published 400 papers and 65 book chapters and pamphlets. He was a technical inventor who established laws that dealt with theories to explain the limited understanding of the effects of radiation on cells. He advocated for methods to improve the therapeutic ratio. As a devout Catholic politician, Dessauer was an early opponent of National Socialism. This led to him being thrown into prison for political reasons in 1933. He did not leave until 1934, and then for Istanbul, largely thanks to Turkish efforts and his appointment as director of a large new institution. While he was already a well-known physicist in Germany, he had to start from scratch in order to build a modern institute. A recent article in the journal Radiotherapy and Oncology celebrated his important contributions to radiology from Turkey. After his contract in Istanbul expired in 1937, he left for the small University of Fribourg in Switzerland, where he was unfortunately unable to continue his scientific productivity. Dessauer wrote textbooks as well as political and philosophical books, and attempted to bridge the gap between Catholicism and science. Additionally, after the war, he began to teach again in Frankfurt. In photos of Dessauer, radiation-induced skin changes on his face and hands were clearly visible. Towards the end of his life, he received many medals and honors for his achievements in Germany, some of them posthumously.

Pioneer factors: nature or nurture?

Chromatin is densely packed with nucleosomes, which limits the accessibility of many chromatin-associated proteins. Pioneer factors (PFs) are usually viewed as a special group of sequence-specific transcription factors (TFs) that can recognize nucleosome-embedded motifs, invade compact chromatin, and generate open chromatin regions. Through this process, PFs initiate a cascade of events that play key roles in gene regulation and cell differentiation. A current debate in the field is if PFs belong to a unique subset of TFs with intrinsic "pioneering activity", or if all TFs have the potential to function as PFs within certain cellular contexts. There are also different views regarding the key feature(s) that define pioneering activity. In this review, we present evidence from the literature related to these alternative views and discuss how to potentially reconcile them. It is possible that both intrinsic properties, like tight nucleosome binding and structural compatibility, and cellular conditions, like concentration and co-factor availability, are important for PF function.

CUX1 regulates human hematopoietic stem cell chromatin accessibility via the BAF complex.

CUX1 is a homeodomain-containing transcription factor that is essential for the development and differentiation of multiple tissues. CUX1 is recurrently mutated or deleted in cancer, particularly in myeloid malignancies. However, the mechanism by which CUX1 regulates gene expression and differentiation remains poorly understood, creating a barrier to understanding the tumor-suppressive functions of CUX1. Here, we demonstrate that CUX1 directs the BAF chromatin remodeling complex to DNA to increase chromatin accessibility in hematopoietic cells. CUX1 preferentially regulates lineage-specific enhancers, and CUX1 target genes are predictive of cell fate in vivo. These data indicate that CUX1 regulates hematopoietic lineage commitment and homeostasis via pioneer factor activity, and CUX1 deficiency disrupts these processes in stem and progenitor cells, facilitating transformation.

Gene regulation by the tumor suppressor p53 - The omics era.

The transcription factor p53 is activated in response to a variety of cellular stresses and serves as a prominent and potent tumor suppressor. Since its discovery, we have sought to understand how p53 functions as both a transcription factor and a tumor suppressor. Two decades ago, the field of gene regulation entered the omics era and began to study the regulation of entire genomes. The omics perspective has greatly expanded our understanding of p53 functions and has begun to reveal its gene regulatory network. In this mini-review, I discuss recent insights into the p53 transcriptional program from high-throughput analyses.

Imagining in Time: The Legacy of Olive Berger (1898-1981).

Olive Berger was a true nurse anesthesia pioneer for our profession. She dedicated her life to the advancement of nurse anesthesia through her leadership, advocacy, scholarly writing, clinical achievements and innovation. She blazed the trail by forming and establishing education requirements for nurse anesthesia programs, established a state nurse anesthesia organization, and led the American Association of Nurse Anesthetists as its 14th president in 1958. She was the Chief Certified Registered Nurse Anesthetist and Program Director at the Johns Hopkins Hospital and is best known for her collaboration with surgeons Dr. Alfred Blalock and Dr. Helen Taussig, providing anesthesia care during the groundbreaking repair of tetralogy of Fallot on infants.

Pioneer plants enhance soil multifunctionality by reshaping underground multitrophic community during natural succession of an abandoned rare earth mine tailing.

Spontaneous natural succession in metal mine tailings is fundamental to the rehabilitation of bare tailing. Here, an abandoned rare earth element (REE) mine tailing with spontaneous colonisation by pioneer plants with different functional traits was selected. Soil nutrient cycling, fertility, organic matter decomposition as well as underground organismal communities and their multitrophic networks were investigated. Compared with the bare tailing, the colonisation with Lycopodium japonicum, Miscanthus sinensis, and Dicranopteris dichotoma increased soil multifunction by 222%, 293%, and 525%, respectively. This was accompanied by significant changes in soil bacterial and protistan community composition and increased soil multitrophic network complexity. Rhizospheres of different plant species showed distinct microbial community composition compared to that of bare tailing. Some WPS-2, Chloroflexi, and Chlorophyta were mainly present in the bare tailing, while some Proteobacteria and Cercozoa were predominantly seen in the rhizosphere. Pearson correlation and Random Forest revealed the biotic factors driving soil multifunction. Structural equation modelling further revealed that pioneer plants improved soil multifunction primarily by decreasing the microbial biodiversity and increasing the multitrophic network complexity. Overall, this highlights the importance of subterrestrial organisms in accelerating soil rehabilitation during natural succession and provides options for the ecological restoration of degraded REE mining areas.

Water level drawdown induces a legacy effect on the seed bank and retains sediment chemistry in a eutrophic clay wetland.

The lack of extreme water level fluctuations in managed, non-peat forming wetland ecosystems can result in decreased productivity through the loss of heterogeneity of these ecosystems. Stochastic disruption, such as a water level drawdown, can effectively reverse this effect and return the wetland to a more productive state, associated with higher biodiversity through new vegetation development. Yet, aside from the effect on vegetation dynamics, little is known about longer-term effects (30 years) of a water level drawdown, hereafter referred to as legacy effects, and how this may impact future water level drawdowns. Here, we aim to unravel the legacy effects of a water level drawdown, stand alone and along a water level gradient, on seed bank properties and nutrient availability in a eutrophic clay wetland. To identify these, we studied the hydrologically managed nature reserve Oostvaardersplassen in the Netherlands. Here, one section was subjected to a multi-year water level drawdown and another section was kept inundated. We determined seed bank properties in both areas, spatially and along a soil elevation gradient (20 cm). Nutrient availability was measured by taking sediment samples along the water level gradient and through experimental manipulation of the water level in an indoor mesocosm experiment. Germination was higher in locations with a water level drawdown history, especially at relatively high elevations. Additionally, the proportion of pioneer species in the seed bank was higher in the water level drawdown area. Overall, nutrient concentrations were higher compared to other aquatic systems. Nutrient availability was higher in the inundated area and did not respond to the water level gradient. We conclude that 30 years after an induced water level drawdown there is no depletion of nutrients, while we still observe a legacy effect in the number of viable seeds in the seed bank.

Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability in Drosophila melanogaster.

Pioneer factors are critical for gene regulation and development because they bind chromatin and make DNA more accessible for binding by other transcription factors. The pioneer factor Grainy head (Grh) is present across metazoans and has been shown to retain a role in epithelium development in fruit flies, nematodes, and mice despite extensive divergence in both amino acid sequence and length. Here, we investigate the evolution of Grh function by comparing the effects of the fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) Grh orthologs on chromatin accessibility, gene expression, embryonic development, and viability in transgenic D. melanogaster. We found that the Caenorhabditis elegans ortholog rescued cuticle development but not full embryonic viability in Drosophila melanogaster grh null mutants. At the molecular level, the C. elegans ortholog only partially rescued chromatin accessibility and gene expression. Divergence in the disordered N-terminus of the Grh protein contributes to these differences in embryonic viability and molecular phenotypes. These data show how pioneer factors can diverge in sequence and function at the molecular level while retaining conserved developmental functions at the organismal level.

Research Protocol for an Observational Health Data Analysis on the Adverse Events of Systemic Treatment in Patients with Metastatic Hormone-sensitive Prostate Cancer: Big Data Analytics Using the PIONEER Platform.

Combination therapies in metastatic hormone-sensitive prostate cancer (mHSPC), which include the addition of an androgen receptor signaling inhibitor and/or docetaxel to androgen deprivation therapy, have been a game changer in the management of this disease stage. However, these therapies come with their fair share of toxicities and side effects. The goal of this observational study is to report drug-related adverse events (AEs), which are correlated with systemic combination therapies for mHSPC. Determining the optimal treatment option requires large cohorts to estimate the tolerability and AEs of these combination therapies in "real-life" patients with mHSPC, as provided in this study. We use a network of databases that includes population-based registries, electronic health records, and insurance claims, containing the overall target population and subgroups of patients defined by unique certain characteristics, demographics, and comorbidities, to compute the incidence of common AEs associated with systemic therapies in the setting of mHSPC. These data sources are standardised using the Observational Medical Outcomes Partnership Common Data Model. We perform the descriptive statistics as well as calculate the AE incidence rate separately for each treatment group, stratified by age groups and index year. The time until the first event is estimated using the Kaplan-Meier method within each age group. In the case of episodic events, the anticipated mean cumulative counts of events are calculated. Our study will allow clinicians to tailor optimal therapies for mHSPC patients, and they will serve as a basis for comparative method studies.

Representativeness of the PIONEER-HF and PARAGLIDE-HF in patients hospitalized with acute heart failure.

AIMS: The PIONEER-HF and PARAGLIDE-HF trials aimed to determine the efficacy and safety of the in-hospital initiation of sacubitril/valsartan in patients hospitalized for AHF. However, whether the inclusion and exclusion criteria of the trials apply to patients encountered in real-world routine care is unclear. This study aimed to investigate the applicability of the PIONEER-HF and PARAGLIDE-HF trials to real-world AHF patients. METHODS AND RESULTS: We identified 28 293 AHF hospitalized patients between August 2008 to August 2017 from the Chang Gung Research Database and classified them into four groups based on left ventricular ejection fraction (LVEF) and trial criteria. Cox proportional hazards models were used to compare the risk of HF hospitalization and cardiovascular (CV) death. We defined PIONEER-HF eligible (n = 3683) and non-eligible (n = 3502) patients with an LVEF ≤40%, and PARAGLIDE-HF eligible (n = 5191) and non-eligible (n = 5832) patients with an LVEF >40%. Over a mean follow-up of 3.5 years, the PIONEER-HF non-eligible and eligible groups exhibited similar rates of HF hospitalization and CV death (41.1% vs. 41.8%, adjusted hazard ratio [aHR]: 0.95; 95% CI: 0.88-1.04). No significant difference was found in the composite outcome between PARAGLIDE-HF non-eligible and eligible groups (36.7% vs. 38.6%; aHR: 0.97; 95% CI: 0.90-1.04). CONCLUSIONS: Using trial criteria, only 31.3% of AHF patients were eligible for sacubitril-valsartan. Yet, non-eligible patients demonstrated similar outcomes to eligible patients, indicating a need for further evaluation of sacubitril-valsartan benefits in non-eligible AHF patients.

Integrative analysis of transcriptomic and epigenomic data reveals distinct patterns for developmental and housekeeping gene regulation.

BACKGROUND: Regulation of transcription is central to the emergence of new cell types during development, and it often involves activation of genes via proximal and distal regulatory regions. The activity of regulatory elements is determined by transcription factors (TFs) and epigenetic marks, but despite extensive mapping of such patterns, the extraction of regulatory principles remains challenging. RESULTS: Here we study differentially and similarly expressed genes along with their associated epigenomic profiles, chromatin accessibility and DNA methylation, during lineage specification at gastrulation in mice. Comparison of the three lineages allows us to identify genomic and epigenomic features that distinguish the two classes of genes. We show that differentially expressed genes are primarily regulated by distal elements, while similarly expressed genes are controlled by proximal housekeeping regulatory programs. Differentially expressed genes are relatively isolated within topologically associated domains, while similarly expressed genes tend to be located in gene clusters. Transcription of differentially expressed genes is associated with differentially open chromatin at distal elements including enhancers, while that of similarly expressed genes is associated with ubiquitously accessible chromatin at promoters. CONCLUSION: Based on these associations of (linearly) distal genes' transcription start sites (TSSs) and putative enhancers for developmental genes, our findings allow us to link putative enhancers to their target promoters and to infer lineage-specific repertoires of putative driver transcription factors, within which we define subgroups of pioneers and co-operators.

Migration patterns of heavy metals from solid waste stockpile soils by native plants for ecological restoration in arid and semi-arid regions of Northwest China.

Ecological remediation with native plants is the main measure to control the pollution of solid waste in Northwest China. However, the heavy metal transport characteristics of these native plants are still unidentified. This study analyzed the distribution of 16 heavy metals in native plants in the desulfurization gypsum yard (DGY), the gangue yard (GY) and the fly ash yard (FAY). The results showed that the soil contained many heavy metals in high concentrations. For instance, As concentrations were comparable to the global soil background values, whereas Cr and Mn concentrations in the area were 2-3 times greater than the global soil background values. The content of heavy metals in the plant root system increased first, then decreased as the distance from the yard increased. Ni, Pb, and Cd migrated well in Artemisia frigida Willd and Artemisia sieversiana Ehrhart ex Willd, with A. sieversiana showing a particularly strong migration in GY. A. sieversiana, on the other hand, was more successful at migrating Cd at DGY and had a similar capability for Mg migration in all three locations. Festuca rubra L was potentially suitable for planting in GY for Ni removal. In conclusion, the migration patterns of different heavy metals were not alike for plants in the three landfills. The results provided a basis for plant selection for ecological restoration in arid and semi-arid regions.