Control of Arabidopsis apical-basal embryo polarity by antagonistic transcription factors.

Plants, similarly to animals, form polarized axes during embryogenesis on which cell differentiation and organ patterning programs are orchestrated. During Arabidopsis embryogenesis, establishment of the shoot and root stem cell populations occurs at opposite ends of an apical-basal axis. Recent work has identified the PLETHORA (PLT) genes as master regulators of basal/root fate, whereas the master regulators of apical/shoot fate have remained elusive. Here we show that the PLT1 and PLT2 genes are direct targets of the transcriptional co-repressor TOPLESS (TPL) and that PLT1/2 are necessary for the homeotic conversion of shoots to roots in tpl-1 mutants. Using tpl-1 as a genetic tool, we identify the CLASS III HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP III) transcription factors as master regulators of embryonic apical fate, and show they are sufficient to drive the conversion of the embryonic root pole into a second shoot pole. Furthermore, genetic and misexpression studies show an antagonistic relationship between the PLT and HD-ZIP III genes in specifying the root and shoot poles

Master Regulators, Regulatory Networks, and Pathways of Glioblastoma Subtypes

Glioblastoma multiforme (GBM) is the most common malignant brain tumor. GBM samples are classified into subtypes based on their transcriptomic and epigenetic profiles. Despite numerous studies to better characterize GBM biology, a comprehensive study to identify GBM subtype-specific master regulators, gene regulatory networks, and pathways is missing. Here, we used FastMEDUSA to compute master regulators and gene regulatory networks for each GBM subtype. We also ran Gene Set Enrichment Analysis and Ingenuity Pathway Analysis on GBM expression dataset from The Cancer Genome Atlas Project to compute GBM- and GBM subtype-specific pathways. Our analysis was able to recover some of the known master regulators and pathways in GBM as well as some putative novel regulators and pathways, which will aide in our understanding of the unique biology of GBM subtypes

Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte

The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumors), is mainly due to the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non- tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus, must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. In particular, we will focus on hepatocyte and describe the pivotal role in the control of EMT/MET dynamics exerted by a tissue-specific molecular mini-circuitry. Recent evidence, indeed, highlighted as two transcriptional factors, the master gene of EMT Snail, and the master gene of hepatocyte differentiation HNF4α, exhorting a direct reciprocal repression, act as pivotal elements in determining opposite cellular outcomes. The different balances between these two master regulators, further integrated by specific microRNAs, in fact, were found responsible for the EMT/METs dynamics as well as for the preservation of both hepatocyte and stem/precursor cells identity and differentiation. Overall these findings impact the maintenance of stem cells and differentiated cells both in in vivo EMT/MET physio-pathological processes as well as in culture.The complex spatial and paracrine relationships between the various liver histotypes are essential for proper functioning of the hepatic parenchymal cells. Only within a correct tissue organization, in fact, they stably maintain their identity and differentiated phenotype. The loss of histotype identity, which invariably occurs in the primary hepatocytes in culture, or in vivo in particular pathological conditions (fibrosis and tumors), is mainly due to the phenomenon of epithelial-to-mesenchymal transition (EMT). The EMT process, that occurs in the many epithelial cells, appears to be driven by a number of general, non- tissue-specific, master transcriptional regulators. The reverse process, the mesenchymal-to epithelial transition (MET), as yet much less characterized at a molecular level, restores specific epithelial identities, and thus, must include tissue-specific master elements. In this review, we will summarize the so far unveiled events of EMT/MET occurring in liver cells. I

Essential amino acids: master regulators of nutrition and environmental footprint?

The environmental footprint of animal food production is considered several-fold greater than that of crops cultivation. Therefore, the choice between animal and vegetarian diets may have a relevant environmental impact. In such comparisons however, an often neglected issue is the nutritional value of foods. Previous estimates of nutrients\u2019 environmental footprint had predominantly been based on either food raw weight or caloric content, not in respect to human requirements. Essential amino acids (EAAs) are key parameters in food quality assessment. We re-evaluated here the environmental footprint (expressed both as land use for production and as Green House Gas Emission (GHGE), of some animal and vegetal foods, titrated to provide EAAs amounts in respect to human requirements. Production of high-quality animal proteins, in amounts sufficient to match the Recommended Daily Allowances of all the EAAs, would require a land use and a GHGE approximately equal, greater o smaller (by only \ub11-fold), than that necessary to produce vegetal proteins, except for soybeans, that exhibited the smallest footprint. This new analysis downsizes the common concept of a large advantage, in respect to environmental footprint, of crops vs. animal foods production, when human requirements of EAAs are used for reference

Systemic Microgravity Response: Utilizing GeneLab to Develop Hypotheses for Spaceflight Risks

Biological risks associated with microgravity is a major concern for space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. The overall goal of our work is to identify potential master regulators responsible for such responses to microgravity conditions. To do this we utilized the NASA GeneLab database which contains a wide array of omics experiments, including data from: 1) different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); 2) different tissues; and 3) different types of assays that measure epigenetic, transcriptional, and protein expression changes. We have performed meta-analysis identifying potential master regulators involved with systemic responses to microgravity. The analysis used 7 different murine and rat data sets, examining the following tissues: liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius). Using a systems biology approach, we were able to determine that p53 and immune related pathways appear central to pan-tissue microgravity responses. Evidence for a universal response in the form of consistency of change across tissues in regulatory pathways was observed in both STS and ISS experiments with varying durations; while degree of change in expression of these master regulators varied across species and strain, some change in these master regulators was universally observed. Interestingly, certain skeletal muscle (gastrocnemius and soleus) show an overall down-regulation in these genes, while in other types (extensor digitorum longus, tibialis anterior and quadriceps) they are up-regulated, suggesting certain muscle tissues may be compensating for atrophy responses caused by microgravity. Studying these organtissue-specific perturbations in molecular signaling networks, we demonstrate the value of GeneLab in characterizing potential master regulators associated with biological risks for spaceflight

Master regulators of FGFR2 signalling and breast cancer risk.

The fibroblast growth factor receptor 2 (FGFR2) locus has been consistently identified as a breast cancer risk locus in independent genome-wide association studies. However, the molecular mechanisms underlying FGFR2-mediated risk are still unknown. Using model systems we show that FGFR2-regulated genes are preferentially linked to breast cancer risk loci in expression quantitative trait loci analysis, supporting the concept that risk genes cluster in pathways. Using a network derived from 2,000 transcriptional profiles we identify SPDEF, ERα, FOXA1, GATA3 and PTTG1 as master regulators of fibroblast growth factor receptor 2 signalling, and show that ERα occupancy responds to fibroblast growth factor receptor 2 signalling. Our results indicate that ERα, FOXA1 and GATA3 contribute to the regulation of breast cancer susceptibility genes, which is consistent with the effects of anti-oestrogen treatment in breast cancer prevention, and suggest that fibroblast growth factor receptor 2 signalling has an important role in mediating breast cancer risk.This is the final version of the article. It was originally published in Nature Communications here: http://www.nature.com/ncomms/2013/130917/ncomms3464/full/ncomms3464.html

Multiple feedback loops through cytokinin signaling control stem cell number within the Arabidopsis shoot meristem

A central unanswered question in stem cell biology, both in plants and in animals, is how the spatial organization of stem cell niches are maintained as cells move through them. We address this question for the shoot apical meristem (SAM) which harbors pluripotent stem cells responsible for growth of above-ground tissues in flowering plants. We find that localized perception of the plant hormone cytokinin establishes a spatial domain in which cell fate is respecified through induction of the master regulator WUSCHEL as cells are displaced during growth. Cytokinin-induced WUSCHEL expression occurs through both CLAVATA-dependent and CLAVATA-independent pathways. Computational analysis shows that feedback between cytokinin response and genetic regulators predicts their relative patterning, which we confirm experimentally. Our results also may explain how increasing cytokinin concentration leads to the first steps in reestablishing the shoot stem cell niche in vitro

A conserved filamentous assembly underlies the structure of the meiotic chromosome axis.

The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that 'axis core proteins' from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify 'closure motifs' in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control

Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis