Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/
HNRNPA1 regulates HMGCR alternative splicing and modulates cellular cholesterol metabolism.
Sex, Subject
View SamplesRNASeq data from WT, Zmym2 knockout- and Zmym2 overexpressing- E14tg2a mouse embryonic stem cells Overall design: RNASeq of ESCs in medium containing Serum and Leukaemia Inhibitory Factor (LIF)
ZMYM2 inhibits NANOG-mediated reprogramming.
Subject
View SamplesIron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity 2,3. Here we identify anon-demand mechanism specific to the liver that clears erythrocytes and recycles iron. We showthat Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kuppfer cells, and depend on Csf1 and Nrf2. The spleenlikewise recruits iron-loaded Ly-6Chigh monocytes, but they do not differentiate into ironrecycling macrophages due to the suppressive action of Csf2, and are instead shuttled to the livervia coordinated chemotactic cues. Inhibiting this mechanism by preventing monocyte recruitment to the liver leads to kidney failure and liver damage. These observations identify the liver as the primary organ supporting emergency erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.
On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver.
Specimen part
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain.
Specimen part
View SamplesNanog null neural stem (NS) cells were reprogrammed to naive pluripotency in 2i/LIF conditions with mouse (m) Nanog and human (h) Nanog. Global gene expression in resulting iPS cells was compared to embryonic stem (ES) cells and nanog null NS cells.
Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain.
Specimen part
View SamplesNanog null neural stem (NS) cells were reprogrammed to naive pluripotency in 2i/LIF conditions with chick (c) and zebrafish (z) Nanog orthologs. Global gene expression was compared to iPS cells derived with mouse (m) Nanog.
Reprogramming capacity of Nanog is functionally conserved in vertebrates and resides in a unique homeodomain.
Specimen part
View SamplesTechnologies allowing for specific regulation of endogenous genes are valuable for the study of gene functions and have great potential in therapeutics. We created the CRISPR-on system, a two-component transcriptional activator consisting of a nuclease-dead Cas9 (dCas9) protein fused with a transcriptional activation domain and single guide RNAs (sgRNAs) with complementary sequence to gene promoters. We demonstrate that CRISPR-on can efficiently activate exogenous reporter genes in both human and mouse cells in a tunable manner. In addition, we show that robust reporter gene activation in vivo can be achieved by injecting the system components into mouse zygotes. Furthermore we show that CRISPR-on can activate the endogenous IL1RN, SOX2, and OCT4 genes. The most efficient gene activation was achieved by clusters of 3 to 4 sgRNAs binding to the proximal promoters suggesting their synergistic action in gene induction. Significantly, when sgRNAs targeting multiple genes were simultaneously introduced into cells, robust multiplexed endogenous gene activation was achieved. Genome-wide expression profiling demonstrated high specificity of the system.
Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system.
Cell line
View SamplesNaïve human embryonic stem cells (hESCs) can be derived from primed hESCs or directly from blastocysts, but their X-chromosome state has remained unresolved. We found that the inactive X-chromosome (Xi) of primed hESCs was reactivated in naïve culture conditions. Similar to cells of the blastocyst, resulting naive cells exhibited two active X-chromosomes with XIST expression and chromosome-wide transcriptional dampening, and initiated XIST-mediated X-inactivation upon differentiation. Both establishment and exit from the naïve state (differentiation) happened via an XIST-negative XaXa intermediate. Together, these findings identify a cell culture system for functionally exploring the two X-chromosome dosage compensation processes in early human development: X-dampening and X-inactivation. Furthermore, the naïve state reset Xi abnormalities of primed hESCs, providing cells better suited for downstream applications. However, naïve hESCs displayed differences to the embryo because XIST expression was predominantly mono-allelic instead of bi-allelic, and X-inactivation was non-random, indicating the need for further culture improvement. Overall design: Differentiated naïve human embryonic stem cells and naïve human embryonic stem cells at different passages (Exp1 for late passage, Exp2 for early passage) were subjected to single cell RNA sequencing by the Fluidigm C1 Single-Cell Auto Prep System.
Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma.
Specimen part, Disease, Compound
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Aflatoxin B1 induces persistent epigenomic effects in primary human hepatocytes associated with hepatocellular carcinoma.
Specimen part
View Samples