Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Expression profiles of liver tissues from wild-type and AID transgenic mice exposed to thioacetamide hepatotoxicity

ABSTRACT: AID is an intrinsic DNA mutator enzyme and contributes to tumorigenesis through the accumulation of genetic aberrations. To examine whether mutagenesis induced by AID during inflammation-associated hepatocarcinogenesis depends on the transcriptional levels of the target genes, we performed the gene expression profiling of liver tissues from AID transgenic mice and wild-type mice with and without thioacetamide treatment. AID transgenic mice and wild-type mice were administered with thioacetamide in drinking water for 6 months, and the gene expression levels of their livers are compared.

ORGANISM(S): Mus musculus

SUBMITTER: Tomonori Matsumoto

PROVIDER: E-GEOD-62878 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

Matsumoto Tomonori T Shimizu Takahiro T Nishijima Norihiro N Ikeda Atsuyuki A Eso Yuji Y Matsumoto Yuko Y Chiba Tsutomu T Marusawa Hiroyuki H

Carcinogenesis 20150512 8

Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations ...[more]

PMID: 25969143

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Project description:The activation-induced cytidine deaminase enzyme (AID) is required in germinal center (GC) B cells for somatic hyper-mutation and class switch recombination at the immunoglobulin locus. In GC-B cells, AID is highly expressed, with inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically, irrespective of mutator activity, by directly deaminating 5-methylcytosine (5mC) in concert with base excision repair glycosylases to exchange unmethylated cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, the range and mechanism by which AID promotes pluripotency is not known. Different studies have suggested either a requirement or a lack of function for promoting pluripotency in somatic nuclei following fusion with embryonic stem cells (ESC). Here we tested directly whether AID regulates epigenetic memory, by comparing the relative ability of cells lacking AID to reprogram from a differentiated cell type to an induced pluripotent stem cell (iPSC). We show that loss of AID impacts two distinct steps of reprogramming: First, AID-null cells are transiently hyper-responsive to the reprogramming process. Second, although they initiate expression of pluripotency genes, they fail to stabilize the pluripotent state. The genome of AID-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably up-regulated. MYC target genes are highly enriched in the set of genes hypermethylated and under-expressed in reprogramming cells lacking AID. Recent studies identified a distinctive late step of reprogramming associated with methylation status. AID appears to regulate this step to stabilize the pluripotent state, removing epigenetic memory to promote expression of secondary pluripotency network genes. Transcriptome sequencing of AID-null tail fibroblasts, wildtype tail fibroblasts, AID-null and wildtype tail fibroblasts reprogrammed for three weeks by ectopic expression of transcription factors Oct4, Sox2, KLf4 and cMyc. Methylation profiling by reduced representation bisulphite seuencing of AID-null tail fibroblasts, wildtype tail fibroblasts, AID-null and wildtype tail fibroblasts reprogrammed for three weeks and AID-null and wildtype clones after three weeks of reprogramming (Picked at two weeks)

Project description:The antibody gene mutator AID promiscuously damages oncogenes and B cell identity genes leading to chromosomal translocations and tumorigenesis. Why non-immunoglobulin loci are susceptible to AID activity is unknown. Here we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome, but are predominantly clustered within super-enhancers. Unexpectedly, in these domains AID deaminates highly active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment. Examination of AID activity in human cells via Single Nucleotide Variant discovery in H3K4me3 ChIP-seq data from 26 MSH2-/-; AIDtg; UGItg, 18 AICDA-/- and 2 unmodified RAMOS clonal populations. Examination of PolII mediated long-range interactions via Chia-PET of RAMOS cells (2 sample). Identification of super-enhancers from H3K27Ac ChIP-Seq data from activated B cells (3 replicates and 1 input control) and RAMOS cells (1 sample and 1 input control), 2 preparations of naive and 2 of germinal center (GC) B cells from human tonsilectomy samples. Mapping of regulatory elements in RAMOS based on H3K4me1 (1 sample) and Nipbl (2 replicates) ChIP-Seq. RNA expression analyses of activated B cells from 3 WT and 3 Il4raU/U mice and RAMOS cells (3 replicates). Mapping of long-range interactions by 4C in activated B cells from a WT and an Il4raU/U mouse with the IL4ra and Il21r locus, respectively, as a viewpoint. Mapping of Super-Enhancers in activated B cells from Il4raU/U and WT control mice (2 samples).

Dataset Information

Expression profiles of liver tissues from wild-type and AID transgenic mice exposed to thioacetamide hepatotoxicity

Publications

Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

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