A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia

Anemia is a clinical hallmark and independent risk factor of malaria caused by Plasmodium spp. infection. While it is known that anemia arises from parasite-induced hemolysis, whether and how host metabolic adaptation to malaria regulate anemia severity is less understood. Here we demonstrate that reprogramming of renal iron (Fe) metabolism is a central component of the host metabolic response regulating the pathogenesis of life-threatening malarial anemia. Renal proximal tubule epithelial cells (RPTEC) are the main cell compartment responsible for Fe storage and recycling during Plasmodium infection in mice. Transcriptional reprogramming of RPTEC couples immune resistance to Plasmodium infection to renal Fe export via the induction of the cellular Fe exporter SLC40A1/ferroportin 1. This integrated defense strategy is essential to deliver Fe to erythroblasts and support compensatory erythropoiesis to prevent the development of life-threatening anemia. Failure to mobilize Fe from RPTEC causes AKI and is associated with life-threatening anemia in P. falciparum-infected individuals. These findings reveal an unexpected role of the kidneys in the control of organismal Fe metabolism during malaria.

Apical and basal auxin sources pattern shoot branching in a moss

Shoot branching mechanisms where branches arise in association with leaves – referred to as lateral or axillary branching – evolved by convergence in the sporophyte of vascular plants and the gametophyte of bryophytes, and accompanied independent events of plant architectural diversification. Previously, we showed that three hormonal cues, including auxin, have been recruited independently to co-ordinate branch patterning in flowering plant leafy shoots and moss gametophores (Coudert, Palubicki et al., 2015). Moreover, auxin-mediated apical dominance, which relies on local auxin production, has been proposed as a unifying molecular regulatory mechanism of branch development across land plants. Whilst our previous work in the moss Physcomitrium patens has gathered indirect evidence supporting the notion that auxin synthesized in gametophore apices regulates branch formation at a distance, direct genetic evidence for a role of auxin biosynthesis in gametophore branching control is still lacking. Here, we show that gametophore apex decapitation promotes branch emergence through massive and rapid transcriptional reprogramming of auxin-responsive genes and altering auxin biosynthesis gene activity. Specifically, we identify a subset of P. patens TRYPTOPHAN AMINO-TRANSFERASE (TAR) and YUCCA FLAVIN MONOOXYGENASE-LIKE (YUC) auxin biosynthesis genes expressed in apical and basal regions of the gametophore, and show that they are essential for branch initiation and outgrowth control. Our results demonstrate that local auxin biosynthesis coordinates branch patterning in moss and thus constitutes a shared and ancient feature of shoot architecture control in land plants.

Reactive oxygen species signalling is involved in alkamide-induced altered root development.

Alkamides are alpha unsaturated N-acylamides structurally related to N-acyl ethanolamides (NAEs) and N-acyl-L-homoserine lactones (AHLs). Studies have shown that alkamides induce prominent changes in root architecture, a significant metabolic readjustment, and transcriptional reprogramming. Some alkamide responses have been associated with redox signalling; however, this involvement and ROS sources have not been fully described. We utilized a genetic approach to address ROS signalling in alkamide-induced processes and found that in Arabidopsis, treatment with the alkamide affinin (50μM) increased the in-situ accumulation of H2O2 in lateral root emergence sites and reduced H2O2 accumulation in primary root meristems implying that altered root growth was dependent on endogenous H2O2. Results show that ROS sourced from PRX34, RBOHC and RBOHD were involved in promotion of lateral root emergence by alkamides. RBOHC was required for affinin-induced enhanced root hair expansion. Furthermore, affinin-induced changes in lateral root emergence, but not root hair length, were dependent on a change in extracellular pH. Finally, reverse genetic experiments suggest heterotrimeric G-proteins were involved in plant response to alkamides; nevertheless, further studies with additional higher order G-protein mutants will be required to resolve this question. These results support that alkamides recruit specific ROS signaling programs to mediate alterations in root architecture.

STIM1 is a core trigger of airway smooth muscle remodeling and hyperresponsiveness in asthma

Airway remodeling and airway hyperresponsiveness are central drivers of asthma severity. Airway remodeling is a structural change involving the dedifferentiation of airway smooth muscle (ASM) cells from a quiescent to a proliferative and secretory phenotype. Here, we show up-regulation of the endoplasmic reticulum Ca2+ sensor stromal-interacting molecule 1 (STIM1) in ASM of asthmatic mice. STIM1 is required for metabolic and transcriptional reprogramming that supports airway remodeling, including ASM proliferation, migration, secretion of cytokines and extracellular matrix, enhanced mitochondrial mass, and increased oxidative phosphorylation and glycolytic flux. Mechanistically, STIM1-mediated Ca2+ influx is critical for the activation of nuclear factor of activated T cells 4 and subsequent interleukin-6 secretion and transcription of pro-remodeling transcription factors, growth factors, surface receptors, and asthma-associated proteins. STIM1 drives airway hyperresponsiveness in asthmatic mice through enhanced frequency and amplitude of ASM cytosolic Ca2+ oscillations. Our data advocates for ASM STIM1 as a target for asthma therapy.

Conservation and Diversity in Gibberellin-Mediated Transcriptional Responses Among Host Plants Forming Distinct Arbuscular Mycorrhizal Morphotypes

Morphotypes of arbuscular mycorrhizal (AM) symbiosis, Arum, Paris, and Intermediate types, are mainly determined by host plant lineages. It was reported that the phytohormone gibberellin (GA) inhibits the establishment of Arum-type AM symbiosis in legume plants. In contrast, we previously reported that GA promotes the establishment of Paris-type AM symbiosis in Eustoma grandiflorum, while suppressing Arum-type AM symbiosis in a legume model plant, Lotus japonicus. This raises a hitherto unexplored possibility that GA-mediated transcriptional reprogramming during AM symbiosis is different among plant lineages as the AM morphotypes are distinct. Here, our comparative transcriptomics revealed that several symbiosis-related genes were commonly upregulated upon AM fungal colonization in L. japonicus (Arum-type), Daucus carota (Intermediate-type), and E. grandiflorum (Paris-type). Despite of the similarities, the fungal colonization levels and the expression of symbiosis-related genes were suppressed in L. japonicus and D. carota but were promoted in E. grandiflorum in the presence of GA. Moreover, exogenous GA inhibited the expression of genes involved in biosynthetic process of the pre-symbiotic signal component, strigolactone, which resulted in the reduction of its endogenous accumulation in L. japonicus and E. grandiflorum. Additionally, differential regulation of genes involved in sugar metabolism suggested that disaccharides metabolized in AM roots would be different between L. japonicus and D. carota/E. grandiflorum. Therefore, this study uncovered the conserved transcriptional responses during mycorrhization regardless of the distinct AM morphotype. Meanwhile, we also found diverse responses to GA among phylogenetically distant AM host plants.

Concerto on Chromatin: Interplays of Different Epigenetic Mechanisms in Plant Development and Environmental Adaptation

Epigenetic mechanisms such as DNA methylation, histone post-translational modifications, chromatin remodeling, and noncoding RNAs, play important roles in regulating plant gene expression, which is involved in various biological processes including plant development and stress responses. Increasing evidence reveals that these different epigenetic mechanisms are highly interconnected, thereby contributing to the complexity of transcriptional reprogramming in plant development processes and responses to environmental stresses. Here, we provide an overview of recent advances in understanding the epigenetic regulation of plant gene expression and highlight the crosstalk among different epigenetic mechanisms in making plant developmental and stress-responsive decisions. Structural, physical, transcriptional and metabolic bases for these epigenetic interplays are discussed.

Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury

Peripheral nerve injury induces genome-wide transcriptional reprogramming of first-order neurons and auxiliary cells of dorsal root ganglia (DRG). Accumulating experimental evidence suggests that onset and mechanistic principles of post-nerve injury processes are sexually dimorphic. We examined largely understudied aspects of early transcriptional events in DRG within 24 h after sciatic nerve axotomy in mice of both sexes. Using high-depth RNA sequencing (>50 million reads/sample) to pinpoint sexually dimorphic changes related to regeneration, immune response, bioenergy, and sensory functions, we identified a higher number of transcriptional changes in male relative to female DRG. In males, the decline in ion channel transcripts was accompanied by the induction of innate immune cascades via TLR, chemokine, and Csf1-receptor axis and robust regenerative programs driven by Sox, Twist1/2, and Pax5/9 transcription factors. Females demonstrated nerve injury-specific transcriptional co-activation of the actinin 2 network. The predicted upstream regulators and interactive networks highlighted the role of novel epigenetic factors and genetic linkage to sex chromosomes as hallmarks of gene regulation post-axotomy. We implicated epigenetic X chromosome inactivation in the regulation of immune response activity uniquely in females. Sexually dimorphic regulation of MMP/ADAMTS metalloproteinases and their intrinsic X-linked regulator Timp1 contributes to extracellular matrix remodeling integrated with pro-regenerative and immune functions. Lexis1 non-coding RNA involved in LXR-mediated lipid metabolism was identified as a novel nerve injury marker. Together, our data identified unique early response triggers of sex-specific peripheral nerve injury regulation to gain mechanistic insights into the origin of female- and male-prevalent sensory neuropathies.

The Extracellular Milieu of Toxoplasma 's Lytic Cycle Drives Lab Adaptation, Primarily by Transcriptional Reprogramming

It has been well established that prolonged in vitro cultivation of Toxoplasma gondii augments progression of the lytic cycle. This lab adaptation results in increased capacities to divide, migrate, and survive outside a host cell, all of which are considered host-independent virulence factors.

Salicylic Acid and Nitric Oxide: Insight Into the Transcriptional Regulation of Their Metabolism and Regulatory Functions in Plants

Salicylic acid (SA) and nitric oxide (NO) are key signaling molecules required to activate the plant's innate immunity against abiotic stresses and biotrophic attackers. Stress-induced signaling and accumulation of SA and NO triggers extensive transcriptional reprogramming of defense-related genes, induced biosynthesis of secondary metabolites and anti-microbial compounds, thereby protecting/steering plant growth and immunity. Transcriptional regulation of SA and NO signaling are crucial for fine-tuning important cellular and metabolic functions, thus making plant defense impervious against many pathogens. The development of an impenetrable immune response is often associated with an unavoidable trade-off in the form of active suppression of plant growth and reproduction. Therefore, we highlighted recent advancements and research to unravel transcriptional regulation of SA and NO signaling essential for fulfilling their role as defense signaling molecules. We also emphasized comprehensive knowledge related to transcriptional reprogramming of SA and NO signaling important in strengthening plant growth-immunity trade-off. We also highlighted the progress on SA and NO signaling playing an indispensable role in stimulating plant-microbe interaction to modulate crucial plant functions.

Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching

In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFβ/SMAD, YAP/TAZ, and β-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of β-catenin, with YAP/TAZ governing an essential subprogram of TGFβ-induced phenotype switching. Wnt/β-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ–induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.