To identify genes dysregulated in bipolar disorder (BD1) we carried out global gene expression profiling using whole-genome microarrays. To minimize genetic variation in gene expression levels between cases and controls we compared expression profiles in lymphoblastoid cell lines from monozygotic twin pairs discordant for the disease. We identified 82 genes that were differentially expressed by 1.3-fold in 3 BD1 cases compared to their co-twins, and which were statistically (p 0.05) differentially expressed between the groups of BD1 cases and controls. Using qRT-PCR we confirmed the differential expression of some of these genes, including: KCNK1, MAL, PFN2, TCF7, PGK1, and PI4KCB, in at least 2 of the twin pairs. In contrast to the findings of a previous study by Kakiuchi and colleagues with similar discordant BD1 twin design1 our data do not support the dysregulation of XBP1 and HSPA5. From pathway and gene ontology analysis we identified up-regulation of the WNT signalling pathway and the biological process of apoptosis. The differentially regulated genes and pathways identified in this study may provide insights into the biology of BD1.
Expression profiling in monozygotic twins discordant for bipolar disorder reveals dysregulation of the WNT signalling pathway.
Sex
View SamplesThe expression level for 15 887 transcripts in lymphoblastoid cell lines from 19 monozygotic twin pairs (10 male, 9 female) were analysed for the effects of genotype and sex. On an average, the effect of twin pairs explained 31% of the variance in normalized gene expression levels, consistent with previous broad sense heritability estimates. The effect of sex on gene expression levels was most noticeable on the X chromosome, which contained 15 of the 20 significantly differentially expressed genes. A high concordance was observed between the sex difference test statistics and surveys of genes escaping X chromosome inactivation. Notably, several autosomal genes showed significant differences in gene expression between the sexes despite much of the cellular environment differences being effectively removed in the cell lines. A publicly available gene expression data set from the CEPH families was used to validate the results. The heritability of gene expression levels as estimated from the two data sets showed a highly significant positive correlation, particularly when both estimates were close to one and thus had the smallest standard error. There was a large concordance between the genes significantly differentially expressed between the sexes in the two data sets. Analysis of the variability of probe binding intensities within a probe set indicated that results are robust to the possible presence of polymorphisms in the target sequences.
Replicated effects of sex and genotype on gene expression in human lymphoblastoid cell lines.
Sex
View SamplesTo better characterize the role of whole pericardial adipose tissue (PCAT) in the pathogenesis of disease, we performed a large-scale unbiased analysis of the transcriptional differences between pericardial and subcutaneous adipose tissue, analysing 53 microarrays across 19 individuals.
Pattern specification and immune response transcriptional signatures of pericardial and subcutaneous adipose tissue.
Specimen part, Subject
View SamplesGM-CSF signaling was previously reported to have a negative effect on a murine model of (8;21)-induced leukemia. Gene expression profiling of MigR1 (Mig) control and RUNX1-ETO (RE), the oncofusion protein generated from t(8;21), murine Lin-/c-Kit+ hematopoietic stem/progenitor cells (HSPCs) was conducted to further elucidate the mechanisms mediating the negative effect induced by GM-CSF signaling in t(8;21) cells,
Restoration of MYC-repressed targets mediates the negative effects of GM-CSF on RUNX1-ETO leukemogenicity.
Specimen part, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Programming human pluripotent stem cells into white and brown adipocytes.
Specimen part, Disease
View SamplesThe utility of human pluripotent stem cells as a tool for understanding disease and as a renewable source of cells for transplantation therapies is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into adipocytes. We found that inducible expression of PPARG2 in pluripotent stem cell-derived mesenchymal progenitor cells programmed their development towards an adipocyte cell fate. Using this approach, multiple human pluripotent cell lines were differentiated into adipocytes with efficiencies of 85% to 90%. These pluripotent stem cell-derived adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers, and exhibited mature functional properties such as lipid catabolism in response to a beta-adrenergic stimulus. Global transcriptional and lipid metabolomic analyses further confirmed the identity and maturity of these pluripotent stem cell-derived adipocytes.
Programming human pluripotent stem cells into white and brown adipocytes.
Specimen part
View Samples[original title] LMP-420: a novel purine nucleoside analogue with potent cytotoxic effects for chronic lymphocytic leukemia cells and minimal toxicity for normal hematopoietic cells.
LMP-420: a novel purine nucleoside analog with potent cytotoxic effects for CLL cells and minimal toxicity for normal hematopoietic cells.
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View SamplesDown syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes in cells with trisomy 21, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute per cell normalization unmasked global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulated the transcriptional changes seen with triplication of a “Down syndrome critical region” on distal chromosome 21. Absolute exogenous normalized ChIP-seq (ChIP-Rx) also revealed a global increase in histone 3 lysine 27 acetylation caused by HMGN1. Genes most amplified downstream of HMGN1 were enriched for tumor- and developmental stage-specific programs of B-cell acute lymphoblastic leukemia dependent on the cellular context. These data offer a mechanistic explanation for DS transcriptional patterns, and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted. Overall design: SLAM-seq in NALM6 human pre-B cells with engineered HMGN1 overexpression
Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression.
Cell line, Treatment, Subject
View SamplesInnate lymphoid cells (ILCs) comprise three groups of recently identified tissue resident immune cell lineages that play critical roles in protective immune responses and tissue homeostasis. While significant progress has been made in defining the key protein mediators of ILC development and function, how cis-acting epigenetic regulatory elements or long non-coding RNAs (lncRNAs) regulate ILCs is unknown. Herein, we describe a cis-regulatory element demarcated by a novel lncRNA that controls the maturation, function and lineage identity of group 1 ILCs while being dispensable for early ILC development and homeostasis of mature ILC2s and ILC3s. We named this ILC1-restricted lncRNA Rroid. The Rroid locus controls the functional specification and lineage identity of ILC1 by promoting chromatin accessibility and STAT5 deposition at the promoter of its neighboring gene, Id2, in response to the ILC1-specific cytokine IL-15. Overall design: RNA-seq for gene expression in mouse NK cells
Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA.
Specimen part, Subject
View SamplesPostmenopausal hormone therapy (HT) is associated with many diseases and conditions, but the underlying molecular mechanisms involved are incompletely understood. The aim of the current study was to investigate the effect of 4 types of HT on gene transcription. 24 women (6 women in 4 treatment groups) received 2 mg 17-estradiol combined with 1 mg noresthisterone acetate (NETA), 1 mg 17-estradiol combined with 0.5 mg NETA, tibolone, or raloxifene hydrochloride. RNA was isolated from whole blood before treatment (baseline) and after 6 weeks on treatment. The changes in mRNA from baseline to 6 weeks were assessed with a microarray chip.
A microarray study on the effect of four hormone therapy regimens on gene transcription in whole blood from healthy postmenopausal women.
Sex, Specimen part
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