Previous studies in our laboratory demonstrated that the azurophil granule protease neutrophil elastase (NE) cleaves PML-RARA (PR), the fusion protein that initiates acute promyelocytic leukemia (APL). Further, NE deficiency reduces the penetrance of APL in a murine model of this disease. We therefore predicted that NE-mediated PR cleavage might be important for its ability to initiate APL. To test this hypothesis, we generated a mouse expressing NE-resistant PR. These mice developed APL indistinguishable from wild type PR, but with significantly reduced latency (median leukemia-free survival of 274 days versus 473 days for wild type PR, p<0.001). Resistance to proteolysis may increase the abundance of full length PR protein in early myeloid cells, and our previous data suggested that non-cleaved PR may be less toxic to early myeloid cells. Together, these effects appear to increase the leukemogenicity of NE-resistant PR, contrary to our previous prediction. We conclude that NE deficiency may reduce APL penetrance via indirect mechanisms that are still NE dependent.
A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia.
Cell line
View SamplesRNA-seq transcriptome analysis identified a functional requirement for zebrafish Rfx4 in the developing neural floor plate and roof plate. Overall design: Embryos derived from an rfx4uw8013/+ incross were sorted by phenotype into mutant and sibling groups. RNA was prepared from each individual embryo at ~ 25 hpf
Zebrafish Rfx4 controls dorsal and ventral midline formation in the neural tube.
No sample metadata fields
View SamplesRNA-seq transcriptome analysis identified an early requirement for zic2 in periocular neural crest as an activator of alx1, a transcription factor with essential roles in craniofacial and ocular morphogenesis in human and zebrafish Overall design: Embryos derived from a zic2aGBT133/+; zic2bUW1127/+ incross were sorted by presence or absence of coloboma. RNA was prepared from each individual embryo at ~ 25 hpf
Zebrafish zic2 controls formation of periocular neural crest and choroid fissure morphogenesis.
No sample metadata fields
View SamplesThis analysis represents the first comprehensive sampling of germ cells in the developing testis over time, at high-resolution, single-cell depth. From these analyses, we have not only revealed novel genetic regulatory signatures of murine germ cells over time, but have also demonstrated that cell types positive for a single marker gene have the capacity to change dramatically during testis maturation, and therefore cells of a particular “identity” may differ significantly from postnatal to adult life. Overall design: Single-cell suspensions of mammalian testes ranging from PND6 to adult were processed for single-cell RNAseq (10x Genomics Chromium) and libraries were sequenced on a NextSeq500 (Illumina).
Dynamic transcriptome profiles within spermatogonial and spermatocyte populations during postnatal testis maturation revealed by single-cell sequencing.
Age, Disease, Cell line, Subject
View SamplesGlatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GAs biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated antiinflammatory markers (e.g. IL10), and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA.
Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids.
Cell line, Treatment, Time
View SamplesHypoxia signature in Clear cell RCC
Regulation of endocytosis via the oxygen-sensing pathway.
Specimen part, Disease, Disease stage
View SamplesIn this experiment we compared total RNA from two commonly used choriocarcinoma cell lines, JEG3 and BeWo, to identify differentially expressed transcripts.
Microarray analysis of BeWo and JEG3 trophoblast cell lines: identification of differentially expressed transcripts.
No sample metadata fields
View SamplesThe study entails novel bio-marker discovery of Tumor Aggressive Grade signature (TAGs) genes and their role in recurrence free survival of breast cancer (BC) patients. Current BC dataset was used for co-expression analysis of TAGs genes and their role in BC progression. Additionally, recent findings have suggested an importance of structural organization of sense-antisense gene pairs (SAGPs) for transcription, post-transcriptional and post-translational events and their associations with cancer and disease. We studied SAGPs in which both gene partners are protein encoding genes (coding-coding SAGPs), their role in human BC development and demonstrated their potential for BC stratification and prognosis. Based on gene expression and correlation analyses we identified the robust set of breast cancer-relevant SAGPs (BCR-SAGPs). We isolated and characterized the sense-antisense gene signature (SAGS) and evaluated its prognostic potential in various gene expression datasets comprising 1161 BC patients. The methods used included the Cox proportional survival analysis, statistical analysis of clinicopathologic parameters and differential gene expression. The SAGS was effective in identification of BC patients with the most aggressive disease. Independently, we validated the SAGS using 58 RNA samples of breast cancer tumors purchased from OriGene Technologies (Rockville, MD).
Sense-antisense gene-pairs in breast cancer and associated pathological pathways.
Age, Disease, Disease stage
View SamplesThe global gene expression profiles of human umbilical cord blood and adult bone marrow CD34+CD33-CD38-Rho(lo)c-kit+ cells, enriched for hematopoietic stem/progenitor cells (HSC) with CD34+CD33-CD38-Rho(hi) cells, enriched in committed hematopoietic progenitor cells (HPC), were compared to identify candidate regulators of HSC self-renewal versus differentiation fate decisions.
Functional analysis of human hematopoietic stem cell gene expression using zebrafish.
No sample metadata fields
View SamplesAngiopoietin-like protein 4 (ANGPTL4, also referred to as Fiaf) has been proposed as circulating mediator between the gut microbiota and fat storage in adipose tissue. Very little is known about mechanisms of regulation of ANGPTL4 in the colon. Here we show that transcription and subsequent secretion of ANGPTL4 in human T84 and HT-29 colonocytes is highly induced by physiological concentrations of products of bacterial fermentation, the short chain fatty acids (SCFA). Induction of ANGPTL4 by SCFA cannot be mimicked by the histone deacetylase inhibitor Trichostatin A. SCFA induce ANGPTL4 by activating the nuclear receptor PPAR, as shown by use of PPAR antagonist, PPAR knock-down, and transactivation assay, which shows activation of PPAR but not PPAR and PPAR. At concentrations required for PPAR activation and ANGPTL4 induction in colonocytes, SCFA do not stimulate PPAR in mouse 3T3-L1 and human SGBS adipocytes, suggesting that SCFA act as selective PPAR modulators (SPPARM), which is supported by coactivator peptide recruitment assay and structural modelling. Consistent with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin was associated with induction of PPAR target genes and pathways in the colon, as shown by microarray and subsequent gene set enrichment analysis. It can be concluded that 1) SCFA potently stimulate ANGPTL4 synthesis in human colonocytes; 2) SCFA transactivate and bind to PPAR by serving as selective PPAR modulators. Our data point to activation of PPAR as a novel mechanism of gene regulation by SCFA in the colon.
Short-chain fatty acids stimulate angiopoietin-like 4 synthesis in human colon adenocarcinoma cells by activating peroxisome proliferator-activated receptor γ.
Sex, Age, Specimen part
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