Study Of Transcription Factors Research Articles

9366 The Rnf20 Histone Modifier Is A Crucial Mediator Of Pancreatic Beta Cell Identity And Function

Abstract Disclosure: T.H. Pierre: None. Y. Liu: None. M.M. Bethea: None. K. Coutinho: None. C. Hunter: None. Diabetes is characterized by the loss of pancreatic β-cell mass. As diabetes incidence continues to elevate, it is critical that we develop a better understanding of the factors that define functional β-cells in order to improve current therapeutics. One approach is through the study of transcription factors (TFs), which are essential for β-cell development and function. Prior work from our lab and others has examined Islet-1 (Isl1) a LIM-homeodomain TF that is required for the maturation of the endocrine pancreas and adult β-cell function. We have also extensively characterized several Isl1-interacting co-regulators (e.g., Ldb1 and SSBP3) that facilitate its roles in maintaining glucose homeostasis. Most recently, we have identified that Isl1 interacts with the ubiquitin ligases Ring Finger 20 (Rnf20) and Rnf40, whose histone H2B monoubiquitation (H2Bub1) activity support the gene regulatory functions of Isl1. With in vitro experiments, we demonstrated that Rnf20 and Rnf40 are important for glucose stimulated insulin secretion (GSIS) and mediate the expression of β-cell identity genes. Based on these findings, we hypothesize that Isl1-Rnf complexes modify histones to regulate β-cell gene expression and function. To address this hypothesis in vivo, we developed an adult inducible β-cell knockout of Rnf20 (Rnf20Δβ-cell). Rnf20Δβ-cell mice display fasting hyperglycemia and severe glucose intolerance that is driven by impaired GSIS, reduced insulin content, and the dysregulation of critical β-cell genes including Ins1, Ucn3, and Slc2a2. Additionally, loss of Rnf20 perturbs insulin processing and overall β-cell maturation as observed by measurement of proinsulin:insulin ratios, C-peptide levels, and whole islet RNA-seq. Phenotypes exhibited by Rnf20Δβ-cell mice are similar to those observed in Isl1 β-cell knockout mice, and comparative transcriptomics revealed an overlap of 570 genes involved in metabolism, zinc homeostasis, and islet proliferation including Slc30a8 and Matn2, both of which we found are occupied by Isl1 and Rnf20. Collectively, our findings demonstrate the importance of the Rnf20 histone modifier in regulating β-cell function and expand our understanding of the Isl1 regulatory network. Presentation: 6/2/2024

Hif-2α programs oxygen chemosensitivity in chromaffin cells.

The study of transcription factors that determine specialized neuronal functions has provided invaluable insights into the physiology of the nervous system. Peripheral chemoreceptors are neurone-like electrophysiologically excitable cells that link the oxygen concentration of arterial blood to the neuronal control of breathing. In the adult, this oxygen chemosensitivity is exemplified by type I cells of the carotid body, and recent work has revealed one isoform of the hypoxia-inducible transcription factor (HIF), HIF-2α, as having a nonredundant role in the development and function of that organ. Here, we show that activation of HIF-2α, including isolated overexpression of HIF-2α but not HIF-1α, is sufficient to induce oxygen chemosensitivity in adult adrenal medulla. This phenotypic change in the adrenal medulla was associated with retention of extra-adrenal paraganglioma-like tissues resembling the fetal organ of Zuckerkandl, which also manifests oxygen chemosensitivity. Acquisition of chemosensitivity was associated with changes in the adrenal medullary expression of gene classes that are ordinarily characteristic of the carotid body, including G protein regulators and atypical subunits of mitochondrial cytochrome oxidase. Overall, the findings suggest that, at least in certain tissues, HIF-2α acts as a phenotypic driver for cells that display oxygen chemosensitivity, thus linking 2 major oxygen-sensing systems.

Transcription factors in megakaryocytes and platelets.

Transcription factors bind promoter or regulatory sequences of a gene to regulate its rate of transcription. However, they are also detected in anucleated platelets. The transcription factors RUNX1, GATA1, STAT3, NFκB, and PPAR have been widely reported to play key roles in the pathophysiology of platelet hyper-reactivity, thrombosis, and atherosclerosis. These non-transcriptional activities are independent of gene transcription or protein synthesis but their underlying mechanisms of action remain poorly defined. Genetic and acquired defects in these transcription factors are associated with the production of platelet microvesicles that are known to initiate and propagate coagulation and to promote thrombosis. In this review, we summarize recent developments in the study of transcription factors in platelet generation, reactivity, and production of microvesicles, with a focus on non-transcriptional activities of selected transcription factors.

Screening for UV-C irradiation-enhanced transcription factors that regulate the metabolism of phenolic compounds in tomato fruit

Solanum lycopersicum phenylalanine ammonia-lyase 5 (SlPAL5) gene regulates the metabolism of phenolic compounds. The study of transcription factors that regulate the expression of SlPAL5 gene is of great significance to elucidate the regulatory mechanism underlying the biosynthesis of phenolic compounds in tomato fruit induced by UV-C irradiation. Here, yeast one-hybrid library of tomato fruit was constructed, and the yeast one-hybrid technology was used to screen the transcription factors that regulate the expression of SlPAL5, the key gene related to the synthesis of phenolic compounds in tomato fruit. As a result, a transcription factor, SlERF7, was obtained and sequenced, followed by the blast homology analysis. Further experiments confirmed that SlERF7 interacted with the promoter of SlPAL5 gene. In addition, UV-C irradiation significantly increased the expression level of SlERF7. These results indicate that SlERF7, which is regulated by UV-C irradiation, might be involved in regulating the transcription of SlPAL5, which provided foundations for further studying the regulation mechanism of the biosynthesis of phenolic compounds in tomato fruit induced by UV-C irradiation.

Unraveling the Complex Interplay Between Transcription Factors and Signaling Molecules in Thyroid Differentiation and Function, From Embryos to Adults.

Thyroid differentiation of progenitor cells occurs during embryonic development and in the adult thyroid gland, and the molecular bases of these complex and finely regulated processes are becoming ever more clear. In this Review, we describe the most recent advances in the study of transcription factors, signaling molecules and regulatory pathways controlling thyroid differentiation and development in the mammalian embryo. We also discuss the maintenance of the adult differentiated phenotype to ensure the biosynthesis of thyroid hormones. We will focus on endoderm-derived thyroid epithelial cells, which are responsible for the formation of the thyroid follicle, the functional unit of the thyroid gland. The use of animal models and pluripotent stem cells has greatly aided in providing clues to the complicated puzzle of thyroid development and function in adults. The so-called thyroid transcription factors – Nkx2-1, Foxe1, Pax8 and Hhex – were the first pieces of the puzzle identified in mice. Other transcription factors, either acting upstream of or directly with the thyroid transcription factors, were subsequently identified to, almost, complete the puzzle. Among them, the transcription factors Glis3, Sox9 and the cofactor of the Hippo pathway Taz, have emerged as important players in thyroid differentiation and development. The involvement of signaling molecules increases the complexity of the puzzle. In this context, the importance of Bmps, Fgfs and Shh signaling at the onset of development, and of TSH, IGF1 and TGFβ both at the end of terminal differentiation in embryos and in the adult thyroid, are well recognized. All of these aspects are covered herein. Thus, readers will be able to visualize the puzzle of thyroid differentiation with most – if not all – of the pieces in place.

Power-law behavior of transcription factor dynamics at the single-molecule level implies a continuum affinity model.

Single-molecule tracking (SMT) allows the study of transcription factor (TF) dynamics in the nucleus, giving important information regarding the diffusion and binding behavior of these proteins in the nuclear environment. Dwell time distributions obtained by SMT for most TFs appear to follow bi-exponential behavior. This has been ascribed to two discrete populations of TFs-one non-specifically bound to chromatin and another specifically bound to target sites, as implied by decades of biochemical studies. However, emerging studies suggest alternate models for dwell-time distributions, indicating the existence of more than two populations of TFs (multi-exponential distribution), or even the absence of discrete states altogether (power-law distribution). Here, we present an analytical pipeline to evaluate which model best explains SMT data. We find that a broad spectrum of TFs (including glucocorticoid receptor, oestrogen receptor, FOXA1, CTCF) follow a power-law distribution of dwell-times, blurring the temporal line between non-specific and specific binding, suggesting that productive binding may involve longer binding events than previously believed. From these observations, we propose a continuum of affinities model to explain TF dynamics, that is consistent with complex interactions of TFs with multiple nuclear domains as well as binding and searching on the chromatin template.

A Mouse Homolog of Mutant Wasp Responsible for X-Linked Neutropenia Causes Reduced Myeloid Progenitor Activity but Rather Increased Neutrophil Compartment in Bone Marrow

Severe congenital neutropenia (SCN) is characterized by severe neutropenia and recurrent episodes of critical infections. X-linked neutropenia (XLN) is a very rare type of SCN caused by a gain-of-function mutation in the Wiscott-Aldrich syndrome gene (WAS), the product of which (WASp) is expressed only in blood cells, and especially to higher extent during neutrophil maturation. Only four types of WASp mutations in its GBD domain (L270P, S272P, I290T, and I294T) have been described so far, and we reported the first Asian case with WASp-I290T.These mutations are supposed to destroy the autoinhibiting conformation of WASp and aberrantly activates WASp. Two mouse models harboring WASp-L272P or I296T, mouse homologs of XLN WASp, have been developed, but neither could recapitulate neutropenia. Herein, we established a novel knock-in mouse carrying WASp-I292T, a mouse homolog of XLN WASp-I290T, and we combined investigations of its peripheral blood and bone marrow cells with analysis of primary samples and iPS cells derived from a WASp-I290T patient. A proband of XLN had 1.3 x 103/mL WBC with a differential count of 8% neutrophils, 5.3% monocytes, 2.3% eosinophils, 3% basophils, and 80.4% lymphocytes. BM revealed marked myeloid hypoplasia with a slight dysplastic change and maturation arrest at the myelocyte stage, and colony forming ability of BM CD34+cells in methylcellulose containing SCF, IL3, and G-CSF demonstrated profound defects in G- and GM-colonies. The patient-derived iPS cells were developed and were induced to differentiate into HSCs by a coculture over an OP9 monolayer, supplemented with optimal cytokine cocktails. Resulting frequency of CD45+CD34+cells was rather comparable to that from cord blood (CB)-derived iPS cells. However, XLN-iPS-derived CD45+CD34+cells produced 5-fold smaller number of myeloid colonies than CB-iPS-derived thosecells in the same methylcellulose culture. To further gain insight into the underlying abnormalities induced by WASp-I290T, we established a novel knock-in mouse model harboring WASp-I292T, which was obtained from CRISPR/Cas9-engineered mouse ES cells. Unlike XLN patients, but similar to two earlier mouse studies, the WASp-I292T mice had normal count of neutrophils, monocytes, B cells, CD4+ T cells, CD8+ T cells, and NK cells (Figure 1A). Administration of G-CSF into the WASp-I292T mice increased neutrophils to the comparable level to Wt mice. Similarly, lipopolysaccharide increased neutrophils and monocytes comparable to Wtmice. However, WASp-I292T neutrophils possessed a stronger ability of phagocytosis than Wt, when determined by the uptake of fluorescently pre-labeled E. coli(p=0.029) (Figure 1B). Colony forming ability of the bone marrow c-kit+, sca-1+, lin-(KSL) cells in methylcellulose containing EPO, IL-3, IL-6, and SCF was significantly impaired in mut mice (p=0.003) (Figure 1C). In the bone marrow, however, the fraction of granulocyte/monocyte progenitors (GMPs; c-kit+, sca-1-, CD34+, CD16/32-) and pre-neutrophils (c-kit+, Gr-1dim, CXCR2-, CXCR4+) were marginally increased in the mut mice (p=0.052, and p=0.006, respectively), and megakaryocyte/erythroid progenitors (MEP; c-kit+, sca-1-, CD34-, CD16/32-) was slightly decreased in the mut mice (p=0.051) (Figure 1D). These results suggested that granulopoietic potential was basically maintained in the WASp-I292T mice, but the process at the end of neutrophil production or the egression from the bone marrow were impaired. We previously reported that NB4WASp-I290T cells produces significantly fewer neutrophils following ATRA-induced differentiation. In addition, analysis of myeloid-related genes revealed a premature upregulation of C/EBP-epsilon in NB4WASp-I290T cells. Because WASp contains a nuclear localization signal-like motif in the basic domain, and confocal laser microscopy suggested that WASp-I290T preferentially localizes in the nucleus rather than cytoplasm, it is likely that WASp-I290T alters myeloid-related genes by direct or indirect interactions with transcription factors in the nucleus; although detailed mechanisms still remain to be elucidated. As compared with profound defects in XLN-patients, defects in WASp-I290T mice were quite modest, suggesting some compensatory mechanisms in the murine hematopoiesis. Further studies of transcription factors and protein-protein interactions would provide a more precise explanation. Disclosures No relevant conflicts of interest to declare.

Transcriptional Dynamics and Candidate Genes Involved in Pod Maturation of Common Bean (Phaseolus vulgaris L.).

Pod maturation of common bean relies upon complex gene expression changes, which in turn are crucial for seed formation and dispersal. Hence, dissecting the transcriptional regulation of pod maturation would be of great significance for breeding programs. In this study, a comprehensive characterization of expression changes has been performed in two common bean cultivars (ancient and modern) by analyzing the transcriptomes of five developmental pod stages, from fruit setting to maturation. RNA-seq analysis allowed for the identification of key genes shared by both accessions, which in turn were homologous to known Arabidopsis maturation genes and furthermore showed a similar expression pattern along the maturation process. Gene- expression changes suggested a role in promoting an accelerated breakdown of photosynthetic and ribosomal machinery associated with chlorophyll degradation and early activation of alpha-linolenic acid metabolism. A further study of transcription factors and their DNA binding sites revealed three candidate genes whose functions may play a dominant role in regulating pod maturation. Altogether, this research identifies the first maturation gene set reported in common bean so far and contributes to a better understanding of the dynamic mechanisms of pod maturation, providing potentially useful information for genomic-assisted breeding of common bean yield and pod quality attributes.

Transcriptome, transcription factors and transcriptional regulation of leaf senescence

Senescence is the last stage of development of a leaf, and is critical for plants’ evolutionary fitness as nutrient remobilization to other organs of a plant is achieved through this process. The leaf senescence process is believed to be under the control of a highly regulated genetic program which is associated with drastic changes of gene expression. Major breakthroughs in the molecular understanding of leaf senescence have been achieved through analyses of the transcriptome and transcriptional regulations during this process. Changes in gene expression reflect the profound physiological rearrangements and studies of transcription factors have provided intriguing clues for the regulatory network involved. This review summarizes recent progress in transcriptomic analyses and studies on transcriptional regulation of leaf senescence.

Challenges of Decoding Transcription Factor Dynamics in Terms of Gene Regulation.

Technological advances are continually improving our ability to obtain more accurate views about the inner workings of biological systems. One such rapidly evolving area is single cell biology, and in particular gene expression and its regulation by transcription factors in response to intrinsic and extrinsic factors. Regarding the study of transcription factors, we discuss some of the promises and pitfalls associated with investigating how individual cells regulate gene expression through modulation of transcription factor activities. Specifically, we discuss four leading experimental approaches, the data that can be obtained from each, and important considerations that investigators should be aware of when drawing conclusions from such data.

MOBE-ChIP: Probing Cell Type-Specific Binding Through Large-Scale Chromatin Immunoprecipitation.

In multicellular organisms, the initiation and maintenance of specific cell types often require the activity of cell type-specific transcriptional regulators. Understanding their roles in gene regulation is crucial but probing their DNA targets in vivo, especially in a genome-wide manner, remains a technical challenge with their limited expression. To improve the sensitivity of chromatin immunoprecipitation (ChIP) for detecting the cell type-specific signals, we have developed the Maximized Objects for Better Enrichment (MOBE)-ChIP, where ChIP is performed at a substantially larger experimental scale and under low background conditions. Here, we describe the procedure in the study of transcription factors in the model plant Arabidopsis. However, with some modifications, the technique should also be implemented in other systems. Besides cell type-specific studies, MOBE-ChIP can also be used as a general strategy to improve ChIP signals.

Transcription Factor Binding Studies in CD4+ T Cells: siRNA Transfection, Chromatin Immunoprecipitation, and Liquid Luminescent DNA Precipitation Assay.

CD4+ T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans among other responses. The biology of CD4+ T cells is complex because naïve CD4+ T cells can differentiate into various subpopulations with various functions that depend on the milieu. Recently, a new population of IL-9-secreting T cells called Th9 cells has been described. These cells are characterized by their ability to produce IL-9. These cells were described to be involved in parasite infections and allergic inflammation. However, some reports described their presence in the tumor bed in mice and humans. Molecular events that account for Th9 effector properties and differentiation are still elusive. To study these mechanisms, downregulation of gene expression and protein-DNA interaction detection allow to identify and study putative transcription factors regulating gene expression during their differentiation. Here, we describe three methods allowing the study of transcription factors in Th9 cells: siRNA transfection for downregulation of gene expression, and chromatin immunoprecipitation and liquid luminescent DNA precipitation assay to detect protein-DNA interactions.

From Gene Expression To Disease Association

Overall Abstract Association studies have achieved significant progress in mapping hundreds of genetic variants to major psychiatric disorders. But the underlying molecular mechanisms regarding specific genes, pathways involved, and interactions among the genes remain largely unknown. Gene expression and its regulation systems are critical for unraveling the causal relationships. This symposium presents cutting edge studies of brain gene expression regulation and its relevance to disease associations. Hermona Soreq from the Hebrew University of Jerusalem will present a study of microRNA (miR) and pseudogene expression and their roles in psychiatry. A selected group of non-coding pseudogenes (PSGs) carry micro RNA (miR) recognition elements (PSG+MRE) compete with brain-expressed genes for the available miR regulators. Furthermore, SNPs surrounding these coding genes tend to be more abundant in psychiatric patients compared to controls. They used transfection-mediated over-expression of PSG+MRE and GapmeR-directed suppression of selected cholinergic transcripts sharing MREs with them in cultured human cells, and demonstrated bi-directional modulation of the interaction of these transcripts with miRs. The study illustrated functional roles of PSGs+MRE in cholinergic functioning, with potential impact on mental disorders. Seth Ament from the Institute for Systems Biology will present a study of transcription factor (TF) binding targets in the brain. They reconstructed a model for the genomic binding sites and functional target genes of 778 TFs in the human brain by integrating large-scale epigenomics and transcriptomics datasets. Using this model, they predicted master regulator transcription factors and functional non-coding variants associated with risk for bipolar disorder and schizophrenia. They experimentally validated the prediction that a master regulator transcription factor, POU3F2, interacts with a risk-associated SNP to modulate the VRK2 promoter. Chunyu Liu from the University of Illinois at Chicago will present a study of co-expression networks involving noncoding RNAs. They retrieved lncRNAs mapped to the seven major CNV deletion regions known to increase risks of developing schizophrenia and carried out weighted gene co-expression network analysis (WGCNA) using data from Genotype-Tissue Expression (GTEx) and BrainSpan projects to look for co-expression modules that harbor CNV-lncRNAs. They identified coexpression modules that were associated with male reproduction in male individuals and associated with neuronal functions in both male and female individuals. The findings suggest that lncRNAs inside those rare CNVs might play significant temporal and spatial roles in regulating other protein-coding genes and subsequently contribute to schizophrenia risk. Hae Kyung Im from the University of Chicago will present the PrediXcan method, which was developed by him, Nancy Cox, and colleagues. By using genotype to predict expression (or other molecular traits) and correlating them with the trait of interest. They have developed prediction models for gene expression in 40 human tissues using the GTEx and Depression Genes Network data. They also extended the method so that only summary statistics are needed to infer PrediXcan results so that they can perform large meta analysis. Using this new method called MetaXcan they have generated results for 117 phenotypes with publicly available GWAS meta-analysis results.

Mechanisms of transcriptional control of glucose metabolism in hepatocytes

The hepatic tissue plays a key role in the regulation and maintenance of stable blood glucose levels. The liver is the main gluconeogenesis organ of the body and is under constant hormonal control to determine the metabolic activity of hepatocytes. Hormonal signals trigger multiple post-translational regulatory mechanisms that alter the activity of key enzymes of glucose metabolism. A crucial role in the long-term control of glucose production and metabolism is played by pre-translational regulation at the level of gene expression of metabolic enzymes. There is growing evidence that this regulation, which is realised via control of the activity of transcription factors, provides constant adjustment of the body to changing environmental conditions and that its disruption leads to the development of metabolic diseases associated with insulin resistance. Therefore, the study of transcription factors that regulate glucose metabolism in the liver and the search for mechanisms to control them is of great biomedical importance in the context of metabolic disease treatment research.

How does C/EBPα speed up cell reprogramming?

Much of what is known about how mammalian cells decide what to become derives from the study of transcription factor (TF)-induced transdifferentiation and reprogramming into induced pluripotent stem (iPS) cells. Among the plethora of transdifferentiation systems described1 the C/EBPα-induced conversion of lymphoid progenitors as well as of mature B cells into macrophages is probably the most efficient, reaching 100%.2 This lineage switch does not involve an overt retrodifferentiation into embryonic stem cells (ESCs) or haematopoietic stem cells, but the transient activation of genes specific for granulocyte/macrophage precursors (GMPs)2 (and see below).

Transcription factors in the development of myeloid cells

Hematopoietic stem cells give rise to various blood cell types with diverse functions, although these different cell types harbor essentially identical genome sequences. The basis for this cell type diversity is the establishment of specific gene expression patterns through transcription factor regulation. Transcription factors recognize and bind to specific nucleotide sequences in target genes and recruit chromatin modifiers to alter the epigenetic status of these genes, thereby controlling their expression. Dysregulation of these processes can cause diseases such as leukemia. Due to rapid advances in high-throughput experimental techniques including chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA-seq, the study of transcription factors is now entering a new era. In this review, we update the current knowledge of developmental pathways in myeloid cells, particularly mononuclear phagocytes (i.e., monocytes/macrophages and dendritic cells), and the transcription factors known to be required for their development. We subsequently provide an overview of the cooperative and antagonistic mechanisms by which the myeloid transcription factors regulate their target genes, with an emphasis on chromatin biology.

Increasing Coverage of Transcription Factor Position Weight Matrices through Domain-level Homology

Transcription factor-DNA interactions, central to cellular regulation and control, are commonly described by position weight matrices (PWMs). These matrices are frequently used to predict transcription factor binding sites in regulatory regions of DNA to complement and guide further experimental investigation. The DNA sequence preferences of transcription factors, encoded in PWMs, are dictated primarily by select residues within the DNA binding domain(s) that interact directly with DNA. Therefore, the DNA binding properties of homologous transcription factors with identical DNA binding domains may be characterized by PWMs derived from different species. Accordingly, we have implemented a fully automated domain-level homology searching method for identical DNA binding sequences.By applying the domain-level homology search to transcription factors with existing PWMs in the JASPAR and TRANSFAC databases, we were able to significantly increase coverage in terms of the total number of PWMs associated with a given species, assign PWMs to transcription factors that did not previously have any associations, and increase the number of represented species with PWMs over an order of magnitude. Additionally, using protein binding microarray (PBM) data, we have validated the domain-level method by demonstrating that transcription factor pairs with matching DNA binding domains exhibit comparable DNA binding specificity predictions to transcription factor pairs with completely identical sequences.The increased coverage achieved herein demonstrates the potential for more thorough species-associated investigation of protein-DNA interactions using existing resources. The PWM scanning results highlight the challenging nature of transcription factors that contain multiple DNA binding domains, as well as the impact of motif discovery on the ability to predict DNA binding properties. The method is additionally suitable for identifying domain-level homology mappings to enable utilization of additional information sources in the study of transcription factors. The domain-level homology search method, resulting PWM mappings, web-based user interface, and web API are publicly available at http://dodoma.systemsbiology.netdodoma.systemsbiology.net.

Bombyx moriTranscription Factors: Genome-Wide Identification, Expression Profiles and Response to Pathogens by Microarray Analysis

Transcription factors are present in all living organisms, and play vital roles in a wide range of biological processes. Studies of transcription factors will help reveal the complex regulation mechanism of organisms. So far, hundreds of domains have been identified that show transcription factor activity. Here, 281 reported transcription factor domains were used as seeds to search the transcription factors in genomes of Bombyx mori L. (Lepidoptera: Bombycidae) and four other model insects. Overall, 666 transcription factors including 36 basal factors and 630 other factors were identified in B. mori genome, which accounted for 4.56% of its genome. The silkworm transcription factors' expression profiles were investigated in relation to multiple tissues, developmental stages, sexual dimorphism, and responses to oral infection by pathogens and direct bacterial injection. These all provided rich clues for revealing the transcriptional regulation mechanism of silkworm organ differentiation, growth and development, sexual dimorphism, and response to pathogen infection.

Study of transcription factor CCAAT/enhancer binding protein-α (C/EBPα) in adult patients with acute lymphoblastic leukemia

Background Leukemic stem cells have self-renewal property. Identification of genes or signaling pathways involved in self-renewal of leukemic stem cells will promote the development of more effective treatment for acute leukemias. Objectives To assess the prognostic significance of the CCAATT/enhancer binding protein-α (C/EBPα) transcription factor in primary adult patients with acute lymphoblastic leukemia (ALL) and its correlation to prognosis and response to therapy. Participants and methods Forty adult patients with ALL (23 pre-B ALL, one pro-B ALL, four mature B ALL, and 12 T ALL) were recruited from the Hematology Department, Ain Shams University, compared with 25 age-matched and sex-matched healthy controls. All patients were subjected to a complete blood count, blood chemistry, bone marrow (BM) examination, immunophenotyping, cytogenetics, and assessment of the C/EBPα level using real–time PCR at presentation and at D28 of treatment. Patients were followed over a period of 24 months (1–24 ms). Results Compared with controls, patients with ALL at presentation and at follow-up showed a highly significant difference in C/EBPα ( P Conclusion Deficient C/EBPα among patients with ALL may contribute toward its pathogenesis and remission is associated with a significant increase in the C/EBPα level. C/EBPα is an independent prognostic factor and its measurement helps to predict response and contributes significantly toward better management decisions.

Transcriptional regulation of mesencephalic dopaminergic neurons: The full circle of life and death

Since mesencephalic dopaminergic neurons are associated to one of the most prominent human neurodegenerative ailments, Parkinson's disease, the molecular mechanism underlying their development and adult cellular properties has been the subject of intense investigations. Throughout life, transcription factors determine the fate of this neuronal population and control essential processes such as localization in the ventral midbrain, their neurotransmitter phenotype, their target innervations and synapse formation. Studies of transcription factors, such as Nurr1, Pitx3, Engrailed-1/2, and Lmx1a/b, have not only revealed importance of these genes during development, but also roles in the long-term survival and maintenance of these neurons. In this review, we will discuss the function of these transcription factors throughout the life of mesencephalic dopaminergic neurons and their value in the study of the disease mechanism.