The transcription factor Sox10 is an important determinant of oligodendroglial identity and influences oligodendroglial development and characteristics at various stages. Starting from RNA-seq data, we here show that the expression of several voltage-gated ion channels with known expression and important function in oligodendroglial cells depends upon Sox10. These include the Nav1.1, Cav2.2, Kv1.1, and Kir4.1 channels. For each of the four encoding genes, we found at least one regulatory region that is activated by Sox10 in vitro and at the same time bound by Sox10 in vivo. Cell-specific deletion of Sox10 in oligodendroglial cells furthermore led to a strong downregulation of all four ion channels in a mouse model and thus in vivo. Our study provides a clear functional link between voltage-gated ion channels and the transcriptional regulatory network in oligodendroglial cells. Furthermore, our study argues that Sox10 exerts at least some of its functions in oligodendrocyte progenitor cells, in myelinating oligodendrocytes, or throughout lineage development via these ion channels. By doing so, we present one way in which oligodendroglial development and properties can be linked to neuronal activity to ensure crosstalk between cell types during the development and function of the central nervous system.

MicroRNAs (miRNAs) are small non-coding RNAs which contribute to the regulation of many physiological and pathological processes. Conventionally, miRNAs perform their activity in the cytoplasm where they regulate gene expression by interacting in a sequence-specific manner with mature messenger RNAs. Recent studies point to the presence of mature miRNAs in the nucleus. This review summarizes current findings regarding the molecular activities of nuclear miRNAs. These molecules can regulate gene expression at the transcriptional level by directly binding DNA on the promoter or the enhancer of regulated genes. miRNAs recruit different protein complexes to these regions, resulting in activation or repression of transcription, through a number of molecular mechanisms. Hematopoiesis is presented as a paradigmatic biological process whereby nuclear miRNAs possess a relevant regulatory role. Nuclear miRNAs can influence gene expression by affecting nuclear mRNA processing and by regulating pri-miRNA maturation, thus impacting the biogenesis of miRNAs themselves. Overall, nuclear miRNAs are biologically active molecules that can be critical for the fine tuning of gene expression and deserve further studies in a number of physiological and pathological conditions.

Mediator, a multiprotein complex, is an important component of the transcription machinery. In plants, the latest reports from our group and some other studies have established that Mediator functions as a signal processor that conveys transcriptional signals from transcription factors to RNA polymerase II. It has been found to be involved in different developmental and stress-adaptation conditions ranging from embryo, root, and shoot development to flowering and senescence and also in response to different biotic and abiotic stresses. In the last one decade, significant progress has been made in understanding the role of Mediator subunits in root development. They have been shown to transcriptionally regulate development of almost all the components of root system architecture - primary root, lateral root and root hair. Their role has also been appreciated in nutrient acquisition through root. In this review, we have discussed all the known functions of Mediator subunits during root development. We have also highlighted the role of Mediator as a nodal point for processing different hormone signaling that regulate root morphogenesis and growth.

Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.

Treacle ribosome biogenesis factor 1 (TCOF1) is responsible for about 80% of mandibular dysostosis (MD) cases. We have formerly identified a correlation between TCOF1 and CNBP (CCHC-type zinc finger nucleic acid binding protein) expression in human mesenchymal cells. Given the established role of CNBP in gene regulation during rostral development, we explored the potential for CNBP to modulate TCOF1 transcription. Computational analysis for CNBP binding sites (CNBP-BSs) in the TCOF1 promoter revealed several putative binding sites, two of which (Hs791 and Hs2160) overlap with putative G-quadruplex (G4) sequences (PQSs). We validated the folding of these PQSs measuring circular dichroism and fluorescence of appropriate synthetic oligonucleotides. In vitro studies confirmed binding of purified CNBP to the target PQSs (both folded as G4 and unfolded) with Kd values in the nM range. ChIP assays conducted in HeLa cells chromatin detected the CNBP binding to TCOF1 promoter. Transient transfections of HEK293 cells revealed that Hs2160 cloned upstream SV40 promoter increased transcription of downstream firefly luciferase reporter gene. We also detected a CNBP-BS and PQS (Dr2393) in the zebrafish TCOF1 orthologue promoter (nolc1). Disrupting this G4 in zebrafish embryos by microinjecting DNA antisense oligonucleotides complementary to Dr2393 reduced the transcription of nolc1 and recapitulated the craniofacial anomalies characteristic of Treacher Collins Syndrome. Both cnbp overexpression and Morpholino-mediated knockdown in zebrafish induced nolc1 transcription. These results suggest that CNBP modulates the transcriptional expression of TCOF1 through a mechanism involving G-quadruplex folding/unfolding, and that this regulation is active in vertebrates as distantly related as bony fish and humans. These findings may have implications for understanding and treating MD.

Plants tightly control growth of their lateral organs, which led to the concept of apical dominance. However, outgrowth of the dormant lateral primordia is sensitive to the plant\'s nutritional status, resulting in an immense plasticity in plant architecture. While the impact of hormonal regulation on apical dominance is well characterized, the prime importance of sugar signaling to unleash lateral organ formation has just recently emerged. Here, we aimed to identify transcriptional regulators, which control the trade-off between growth of apical versus lateral organs. Making use of locally inducible gain-of-function as well as single and higher-order loss-of-function approaches of the sugar-responsive S1-basic-leucine-zipper (S1-bZIP) transcription factors, we disclosed their largely redundant function in establishing apical growth dominance. Consistently, comprehensive phenotypical and analytical studies of S1-bZIP mutants show a clear shift of sugar and organic nitrogen (N) allocation from apical to lateral organs, coinciding with strong lateral organ outgrowth. Tissue-specific transcriptomics reveal specific clade III SWEET sugar transporters, crucial for long-distance sugar transport to apical sinks and the glutaminase GLUTAMINE AMIDO-TRANSFERASE 1_2.1, involved in N homeostasis, as direct S1-bZIP targets, linking the architectural and metabolic mutant phenotypes to downstream gene regulation. Based on these results, we propose that S1-bZIPs control carbohydrate (C) partitioning from source leaves to apical organs and tune systemic N supply to restrict lateral organ formation by C/N depletion. Knowledge of the underlying mechanisms controlling plant C/N partitioning is of pivotal importance for breeding strategies to generate plants with desired architectural and nutritional characteristics.

The epigenetic factor Methyl-CpG-Binding Protein 2 (MeCP2) is a nuclear protein that binds methylated DNA molecules (both 5-methylcytosine and 5-hydroxymethylcytosine) and controls gene transcription. MeCP2 is an important transcription factor that acts in a dose-dependent manner in the brain; thus, its optimal expression level in brain cells is important. As such, its deregulated expression, as well as gain- or loss-of-function mutation, lead to impaired neurodevelopment, and compromised structure and function of brain cells, particularly in neurons. Studies from others and us have characterized two well-recognized MeCP2 isoforms: MeCP2E1 and MeCP2E2. We have reported that in Daoy medulloblastoma brain cells, MeCP2E2 overexpression leads to MeCP2E1 protein degradation. Whether MeCP2 isoforms regulate the Mecp2 promoter regulatory elements remains unexplored. We previously showed that in Daoy cells, metformin (an anti-diabetic drug) induces MECP2E1 transcripts. However, possible impact of metformin on the Mecp2 promoter activity was not studied. Here, we generated stably transduced Daoy cell reporters to express EGFP driven by the Mecp2 promoter. Transduced cells were sorted into four EGFP-expressing groups (R4-to-R7) with different intensities of EGFP expression. Our results confirm that the Mecp2 promoter is active in Daoy cells, and that overexpression of either isoform inhibits the Mecp2 promoter activity, as detected by flow cytometry and luciferase reporter assays. Interestingly, metformin partially relieved the inhibitory effect of MeCP2E1 on the Mecp2 promoter, detected by flow cytometry. Taken together, our data provide important insight towards the regulation of MeCP2 isoforms at the promoter level, which might have biological relevance to the neurobiology of the brain.

Cell plasticity theoretically extends to all possible cell types, but naturally decreases as cells differentiate, whereas injury-repair re-engages the developmental plasticity. Here we show that the lung alveolar type 2 (AT2)-specific transcription factor (TF), CEBPA, restricts AT2 cell plasticity in the mouse lung. AT2 cells undergo transcriptional and epigenetic maturation postnatally. Without CEBPA, both neonatal and mature AT2 cells reduce the AT2 program, but only the former reactivate the SOX9 progenitor program. Sendai virus infection bestows mature AT2 cells with neonatal plasticity where Cebpa mutant, but not wild type, AT2 cells express SOX9, as well as more readily proliferate and form KRT8/CLDN4+ transitional cells. CEBPA promotes the AT2 program by recruiting the lung lineage TF NKX2-1. The temporal change in CEBPA-dependent plasticity reflects AT2 cell developmental history. The ontogeny of AT2 cell plasticity and its transcriptional and epigenetic mechanisms have implications in lung regeneration and cancer.

MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) that play their roles in the regulation of physiological and pathological processes. Originally, it was assumed that miRNAs only modulate gene expression posttranscriptionally in the cytoplasm by inducing target mRNA degradation. However, with further research, evidence shows that mature miRNAs also exist in the cell nucleus, where they can impact gene transcription and ncRNA maturation in several ways. This review provides an overview of novel models of nuclear miRNA functions. Some of the models remain to be verified by experimental evidence, and more details of the miRNA regulation network remain to be discovered in the future.

The protozoan parasite Entamoeba histolytica causes amoebiasis, a global public health problem. Amoebiasis is solely transmitted by cysts that are produced from proliferative trophozoites by encystation in the large intestine of humans. During encystation, various metabolites, pathways, and cascades sequentially orchestrate the morphological and physiological changes required to produce cysts. Cholesteryl sulfate (CS) has recently been revealed to be among the key molecules that control the morphological and physiological changes of encystation by exerting pleiotropic effects. CS promotes the rounding of encysting Entamoeba cells and maintains this spherical morphology as encysting cells are surrounded by the cyst wall, a prerequisite for resistance against environmental stresses. CS is also involved in the development of membrane impermeability, another prerequisite for resistance. The initiation of cyst wall formation is, however, CS-independent. Here, we overview CS-dependent and -independent processes during encystation and discuss their functional linkage. We also discuss a potential transcriptional cascade that controls the processes necessary to produce dormant Entamoeba cysts.