Unknown,Transcriptomics,Genomics,Proteomics

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Essential role of the transcription factors E2A and E2-2 in germinal center B cell and plasma cell development

ABSTRACT: E2A is an essential regulator of early B-cell development. Here we demonstrated that E2A together with E2-2 controlled germinal-center B-cell and plasma cell development. As shown by identification of regulated E2A,E2-2 targets in activated B-cells, these E-proteins directly activated genes with important functions in germinal-center B-cells and plasma cells by inducing or maintaining DNase I hypersensitive sites. Through controlling multiple enhancers in the Igh 3â regulatory region and Aicda locus, E-proteins regulated class switching by inducing both Igh germline transcription and AID expression. By regulating 3â Igk enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh and Prdm1 activation in plasmablasts. These data identified E2A and E2-2 as central regulators of B-cell immunity. 56 samples in total: A) 38 RNA-Seq samples in 5 cell types: Follicular B cells (FO B cell, 2 genotypes, 2 replicates each) Activated B cells (Act B cell, 2 genoytpes, 6 stimulations, 2 replicates each) Pre-Plasmablasts (Pre-PB, 1 genotype, 2 stimulations, 2 replicates each) Plasmablasts (PB, 1 genotype, 2 stimulations, 2 replicates each) Germline Center B cells (GC B cell, 1 genotype, 2 replicates); B) 13 ChIP-Seq samples in 5 cell types: FO B cell (E2A, 2 crosslinking types, 1 replicate each) Act B cell (E2A, 2 crosslinking types, 2 stimulations, 1 replicate each; H3K27ac, 1 crosslinking type, 1 stimulation, 2 genotypes, 1 replicate each) Pre-PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) PB (E2A, 2 crosslinking types, 1 stimulation, 1 replicate each) Mature B cell (input); C) 5 ATAC Seq samples in 2 cell types: Act B cell (2 stimulations, 2 genotypes, 1 replicate each), Pre-PB (1 stimulation, 1 genotype, 1 replicate).

ORGANISM(S): Mus musculus

SUBMITTER: Markus Jaritz

PROVIDER: E-GEOD-77744 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Defects in homocysteine and folate metabolism are associated with increased risks for neural tube and congenital heart defects, cardiovascular disease and stroke, cancers, and neurodegeneration. In many but not all cases, dietary supplementation with folate significantly reduces the severity and incidence of these conditions. Common polymorphisms modulate these metabolic pathways and disease risks, but do not fully account for the particular birth defects and adult diseases that occur in at-risk individuals. To test whether other pathways contribute to disease pathogenesis, we analyzed global and pathway-specific changes in gene expression and levels of selected metabolites after depletion and repletion of dietary folate in two genetically distinct inbred strains of mice. Compared to the C57BL/6J strain, A/J showed greater homeostatic response to folate perturbation by retaining a higher serum folate level and minimizing global gene expression changes. Remarkably, folate perturbation led to systematic strain-specific differences only in the expression profile of the cholesterol biosynthesis pathway and translated to changes in levels of serum and liver total cholesterol. By genetically increasing serum and liver total cholesterol levels in APOE deficient mice, we modestly but significantly improved folate retention during folate depletion, suggesting an interplay between homocysteine and folate metabolism and cholesterol metabolism. Absence of measurable changes in global methylation patterns or amelioration of effects with supplementation with an alternative methyl donor suggest that dietary folate perturbations do not act through large-scale or general changes in methylation. These results suggest that homeostatic responses in cholesterol metabolism contribute to the beneficial effects of dietary folate supplementation. Keywords: time course, stress response, diet, genetic, homeostasis Six-week old female A/J and C57BL/6J mice were purchased from the Jackson Laboratory. All mice were raised on a control diet containing four ppm folic acid (Basal Diet 5755, TestDiet) for one week before the start of studies. Selected mice were then placed on folic acid deficient diet (58C3, TestDiet) containing 1% succinylsulfathiazole, a non-absorbable antibiotic commonly used to suppress folate production by bacteria in the intestine. We had nine different treatment plans per strain with eight replicate mice per treatment. There were four folic acid depletion treatment in which mice were placed on folic acid deficient diet for 1, 2, 7, or 14 days. There were two folic acid repletion treatment in which mice were placed on folic acid deficient diet for 14 days followed by 1 day on control diet and another set of mice on 14 days of folic acid deficient diet followed by 7 days of control diet. There were three control time points in which mice were placed on the control diet for 0, 9, or 22 days. Eight biological replicate liver tissue from each treatment was pooled and total RNA from each pool and total RNA from Universal Mouse Reference RNA (Stratagene) were aminoallyl labeled with Cy3 and Cy5 in duplicate, with reversing of dyes.

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Essential role of the transcription factors E2A and E2-2 in germinal center B cell and plasma cell development

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