Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase-domain focused CRISPR/Cas9-based genetic screen with a newly optimized sgRNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies. Overall design: A CRISPR-screen reveals HRI kinase as a fetal hemoglobin repressor and further validated in HUDEP2 and CD34+ derived primary erythroid cultures.
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
Specimen part, Disease, Subject
View SamplesElevated levels of microRNA miR-155 represent a candidate pathogenic factor in chronic B-lymphocytic leukemia (B-CLL). In this study, we present evidence that MYB (v-myb myeloblastosis viral oncogene homolog) is overexpressed in a subset of B-CLL patients. MYB physically associates with the promoter of MIR155 host gene (MIR155HG, also known as BIC, B-cell integration cluster) and stimulates its transcription. This coincides with the hypermethylated histone H3K4 residue and spread hyperacetylation of H3K9 at MIR155HG promoter. Our data provide evidence of oncogenic activities of MYB in B-CLL that include its stimulatory role in MIR155HG transcription.
MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia.
Specimen part, Disease, Disease stage
View SamplesFluorescence-activated cell sorting of M4-GFP wing imaginal disc cells was used to recover a purified population of the cells that comprise the proneural clusters from which sensory organ precursors of the peripheral nervous system (PNS) arise. Whole-genome microarray analysis and in situ hybridization was then used to identify and verify a set of genes that are preferentially expressed in proneural cluster cells. Genes in this set encode proteins with a diverse array of implied functions, and loss-of-function analysis of two candidate genes shows that they are indeed required for normal PNS development.
Genetic programs activated by proneural proteins in the developing Drosophila PNS.
No sample metadata fields
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Influence of hyperthyroid conditions on gene expression in extraocular muscles of rats.
No sample metadata fields
View SamplesWe used microarrays to expression profile cardiomyocytes from neonatal Sprague-Dawley rats treated with 1 to 50 ug/mL DEHP and control (0.1% DMSO) to identify changes in gene expression related to connexin-43 expression, calcium handling, arrhythmogenesis and mechanical motion.
Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity.
Age, Specimen part, Treatment
View SamplesWe used microarrays to expression profile cardiomyocytes from neonatal Sprague-Dawley rats treated with 50 ug/mL DEHP and control (0.1% DMSO) to identify changes in gene expression related to connexin-43 expression, calcium handling, arrhythmogenesis and mechanical motion.
Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity.
Age, Specimen part, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Gene expression profiling of DEHP-treated cardiomyocytes reveals potential causes of phthalate arrhythmogenicity.
Age, Specimen part, Treatment
View SamplesExtraocular muscles (EOMs) are a highly specialized type of tissue with a wide range of unique properties, including characteristic innervation, development, and structural proteins. Even though EOMs are frequently and prominently involved in thyroid-associated diseases, little is known about the immediate effects of thyroid hormone on these muscles. In order to create a comprehensive profile of changes in gene expression levels in EOMs induced by thyroid hormone, hyperthyroid conditions were simulated by treating adult Sprague-Dawley rats with intraperitoneal injections of 25 g T3 per 100 g body weight over the course of six weeks; subsequently, microarray analysis was used to determine changes in mRNA levels in EOMs from T3-treated animals relative to untreated controls.
Influence of hyperthyroid conditions on gene expression in extraocular muscles of rats.
No sample metadata fields
View SamplesExtraocular muscles (EOMs) are a highly specialized type of tissue with a wide range of unique properties, including characteristic innervation, development, and structural proteins. Even though EOMs are frequently and prominently involved in thyroid-associated diseases, little is known about the immediate effects of thyroid hormone on these muscles. In order to create a comprehensive profile of changes in gene expression levels in EOMs induced by thyroid hormone, hyperthyroid conditions were simulated by treating adult Sprague-Dawley rats with intraperitoneal injections of 25 g T3 per 100 g body weight over the course of six weeks; subsequently, microarray analysis was used to determine changes in mRNA levels in EOMs from T3-treated animals relative to untreated controls.
Influence of hyperthyroid conditions on gene expression in extraocular muscles of rats.
No sample metadata fields
View SamplesHMGN1 contributes to the shortened latency of liver tumorigenesis by changing a chromatin structure and expression of relevant genes
Loss of the nucleosome-binding protein HMGN1 affects the rate of N-nitrosodiethylamine-induced hepatocarcinogenesis in mice.
Specimen part, Treatment
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