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Epigenetic Regulation of Cell Fate
No full textA fundamental question in biology is to decipher how the same genomic information in an organism can give rise to diverse cellular states that are phenotypically and functionally distinct. Epigenetic mechanisms utilize genomic information to establish unique gene expression patterns that cells acquire in different fates during development or in response to environmental perturbations such as diet. Although it is understood that a particular cell fate-specific gene expression pattern relies on the establishment of a specific chromatin organization that is shaped by the activities of chromatin-modifying enzymes and transcription factors, the precise mechanisms that they employ for epigenetic regulation during cellular differentiation and in response to diet are unclear. Here, we dissect the mechanisms underlying epigenetic regulation of cell fate in two different models: regulation of iNKT cell development by the H3K27me3 histone demethylases and dietary regulation of intestinal stem cell fate.
First, we interrogated the biological significance of H3K27me3 histone demethylases (UTX and JMJD3) during iNKT development. iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. We showed that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development and showed that target genes of both JunB and iNKT master transcription factor PLZF are UTX-dependent. Moreover, we demonstrated that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. Altogether, these findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms.
Second, we assessed the cellular and molecular mechanisms through which pro-obesity diets regulate tissue stem and progenitor cell function. We showed that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells of the mammalian intestine. Mechanistically, we found that a HFD activated the lipid-sensing transcription factor peroxisome proliferator-activated receptor delta (PPAR-δ) in intestinal stem cells and progenitor cells (non-intestinal stem cells) and pharmacological activation of PPAR-δ recapitulated the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhanced the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endowed organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permitted these progenitors to form in vivo tumors after loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors.
Overall, these studies delineate the epigenetic mechanisms that control cell state-specific gene expression patterns through the regulation of transcription by histone-modifying enzymes and transcription factors.Medical SciencesMedical SciencesEpigenetics; stem cells; immunology; cance
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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A bipartite mechanism for IGF2BP1 in regulation of fetal hemoglobin
No full textDespite over a century of work on hemoglobinopathies, among them sickle cell disease, a complete understanding of hemoglobin switching and factors regulating hemoglobin expression remains incomplete even as the first CRISPR/Cas9 gene therapy has obtained approvals for the treatment of transfusion-dependent β-thalassemia and sickle cell disease.
DDX6, an RNA helicase and P-body nucleator associated with miRNA-mediated RNA decay and was identified as an HbF repressor in a genome-wide CRISPR screen performed in our lab. I performed a CRISPR tiling screen on DDX6 using SpRY-ABE8e-Cas9 to achieve near base-pair resolution and identify a well-tolerated variant that induces fetal hemoglobin expression, useful to enable the further study of the role of DDX6 in regulation of fetal hemoglobin.
I studied factors regulating the heterochronically silenced m6A RNA-binding protein IGF2BP1 which has been identified as a positive regulator of fetal hemoglobin expression by suppressing BCL11A expression. In contrast to this observation, post-transcriptional control by IGF2BP1 generally acts through improving the translation and mRNA stability of IGF2BP1 target mRNAs in an m6A-dependent manner. To better characterize the IGF2BP1-mediated mechanism responsible for control of fetal hemoglobin expression, I assessed whether BCL11A was required for IGF2BP1-mediated regulation of fetal hemoglobin and discovered a direct BCL11A-independent mechanism. I developed a luminescent transgenic reporter to disentangle the BCL11A¬¬-dependent and newly identified BCL11A-independent mechanisms and used it discovered that IGF2BP1 directly supports the translation of HBG mRNA in a manner requiring an intact stop codon-proximal m6A motif. In addition to this BCL11A-independent mechanism, I identified that the BCL11A-dependent mechanism relies on IGF2BP1-mediated post-transcriptional control of HIC2, which indirectly supports fetal hemoglobin expression via suppression of BCL11A.
This work establishes a strategy for near-base pair resolution CRISPR base editing screening and validation of variants of interest in a novel fetal hemoglobin reporter cell line. This gene, DDX6, is likely involved in post-transcriptional control of factors regulating fetal hemoglobin. Additionally, I characterize a heretofore misunderstood BCL11A-dependent mechanism for IGF2BP1 in regulating fetal hemoglobin expression while simultaneously identifying a novel direct effect of IGF2BP1 on the fetal hemoglobin RNA, a strategy with potential to be exploited for the improved expression of lentiviral gene therapy vectors delivering HBB for sickle cell disease or transfusion dependent β-thalassemia.Medical SciencesMedical Science
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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