Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The CCR4-NOT complex contributes to repression of Major Histocompatibility Complex class II transcription

ABSTRACT: The multi-subunit CCR4 (carbon catabolite repressor 4)-NOT (Negative on TATA) complex serves as a central coordinator of all different steps of eukaryotic gene expression. Accordingly, members of the CCR4-NOT complex have been implicated in a variety of biological functions. Here we performed a systematic and comparative analysis of cells where the CCR4-NOT subunits CNOT1, CNOT2 or CNOT3 were individually downregulated using doxycycline-inducible shRNAs. Microarray experiments showed that downregulation of either CNOT subunit resulted in elevated expression of major histocompatibility complex class II (MHC II) target genes which are found in a gene cluster on chromosome 6. Increased expression of MHC II genes after knock-down or knock-out of CNOT subunits was seen in a variety of cell systems and also in naïve macrophages from CNOT3 conditional knock-out mice. CNOT2-mediated repression of MHC II genes occurred independent from the master regulator class II transactivator (CIITA) and detectable changes of the chromatin structure at the chromosomal MHC II locus. CNOT2 downregulation resulted in an increased de novo transcription of mRNAs and tethering of CNOT2 to a regulatory region governing MHC II expression resulted in dimished transcription. These results expand the known repertoire of CCR4-NOT members for immune regulation and identify CNOT proteins as a novel group of corepressors serving to restrict inappropriate or exaggerated class II expression, which can be causative for various diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE90474 | GEO | 2017/03/15

SECONDARY ACCESSION(S): PRJNA354784

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Identification of Ccr4-Not complex as a regulator of transition from partial to genuine iPS cells

Project description:Partial induced pluripotent cells (iPSCs) are cell lines strayed from normal route from somatic cells to iPSCs and are immortalized. Mouse partial iPSCs are able to convert to real iPSCs by the exposure to 2i condition using MAPK and GSK3? inhibitors. However, the molecular mechanisms of this conversion are totally not known. Our piggyback vector mediated genome-wide screen revealed that Cnot2, one of core components of Ccr4-Not complex participates in this conversion. Subsequent analyses revealed other core components, i.e., Cnot1 and Cnot3 and Trim28 which is known to extensively share genomic binding sites with Cnot3 contribute to this conversion as well. Our bioinformatics analyses indicate that the major role of these factors in the conversion is the down-regulation of developmental genes in partial iPSCs. Two partial iPSC clones (2B1 and 5C5) cultured under conventional culture condition with leukemia inhibitory factor (LIF) and serum and those converted to iPSCs by the exposure to 2i condition were used for RNA source. Partial iPSCs (2B1) cultured under conventional condition in which either one of Cnot1, Cnot2, Cnot3 and Trim28 cDNA or these factors were combinatorially incorporated after retrovirus infection and those in which empty vector or Nanog were stably integrated were also used for RNA source. In addition, embryonic fibroblasts and embryonic stem cells (ESCs) from 13.5 dpc embryos and blastocysts, respectively, from Nanog-GFP transgenic mice and wild-type ESC line (EBRTcH3) were used for RNA source.

2014-01-07 | E-GEOD-44339 | biostudies-arrayexpress

Identification of Ccr4-Not complex as a regulator of transition from partial to genuine iPS cells

2014-01-07 | GSE44339 | GEO

Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

Project description:Decay of mRNAs initiates with shortening of the poly(A) tail. Although the CCR4-NOT complex participates in deadenylation, how it becomes activates remain obscure. We show that complete deficiency in CNOT3, subunit 3 of this complex, is lethal in mice, but that heterozygotes survive as lean mice with hepatic and adipose tissues containing reduced lipid levels. Cnot3+/- mice have enhanced metabolic rates and remain lean on high-fat diets. We further provide evidence suggesting that CNOT3, by changing its level in response to feeding conditions, affects the activity of the CCR4-NOT deadenylase against poly(A) tails of specific mRNAs coding for proteins involved in metabolism of carbohydrates and fats. Because the levels of CNOT3 protein were decreased under fasting conditions and increased upon refeeding and because CNOT3 could be a positive regulator of the CCR4-NOT deadenylase, we hypothesized that the levels of CCR4-NOT target mRNAs would be lower in fed mice than in fasted mice. We compared the gene expression profiles of fed and fasted wild-type mice. Microarray analysis revealed that approximately 1,200 mRNA transcripts were down-regulated in the livers of fed mice. Of these mRNAs, 68 corresponded to the genes up-regulated in the livers of Cnot3+/- mice and fasted wild-type mice. A large number of the 68 identified genes encoded proteins involved in metabolism, especially lipid metabolism and growth. The livers were isolated from 8-week-old fed wild-type, fasted wild-type and fasted Cnot3+/- mice (n = 2 for each genotype).

2011-12-09 | E-GEOD-18925 | biostudies-arrayexpress

Expression data from A549 human lung adenocarcinoma cells with and without knockdown against CNOT3

Project description:The physiological importance of mRNA degradation through the CCR4-NOT deadenylase has recently been highlighted. For example, mutation in CNOT3, a gene coding for sCNOT3 subunit of the CCR4-NOT complex, is found to be associated with T-cell acute lymphoblastic leukemia, T-ALL, though its contribution to other cancers has not been reported. To identify the taget mRNAs of CNOT3 in human non-small cell lung cancer (NSCLC), we performed the microarray analysis using A549 cells with and without knockdown against CNOT3.

2021-05-19 | GSE114694 | GEO

Rapid CLIP Dissociation from MHC II Promotes an Unusual Antigen Presentation Pathway in Autoimmunity

Project description:A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-Ag7 even in the absence of DM, and this property is related to the type 1 diabetes-associated b57 polymorphism. We generated knock-in Non-obese Diabetic (NOD) mice with a single amino acid change in the CLIP segment of invariant chain in order to moderately slow CLIP dissociation from I-Ag7. These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within b cell secretory granules. Rapid CLIP dissociation enhanced presentation of such extracellular peptides, thus bypassing the conventional MHC class II antigen processing pathway. Autoimmunity-associated MHC class II polymorphisms therefore not only modify binding of self-peptides, but also alter the biochemistry of peptide acquisition.

2018-08-09 | GSE118322 | GEO

Regulation of B cell early development by CNOT3

Project description:The CCR4-NOT complex, bearing poly(A) deadenylation activity, is a highly conserved regulator that is involved in biological control; however its action mechanisms and physiological targets remain unclear. Using genetic deletion of the CNOT3 subunit of this complex in early B cell progenitors, we show that CNOT3 plays a critical role in pro- to pre-B cell transition. CNOT3 participated in controlling germline transcription, compaction of the immunoglobulin heavy chain (Igh) locus, and Igh rearrangement, and in destabilizing tumor suppressor p53 mRNA. Moreover, by genetic ablation of p53 or introduction of pre-rearranged Igh transgene, the B cell developmental defect in the Cnot3 knockout background could be partly rescued, suggesting that CCR4-NOT complex exerts critical control in B cell differentiation processes by co-utilizing transcriptional and post-transcriptional mechanisms. Pro-B cells mRNA profiles of Mb1(cre/+) and Cnot3(fl/fl)Mb1(cre/+) mice were generated by deep sequencing using Illumina HiSeq 1500

2015-07-23 | E-GEOD-64455 | biostudies-arrayexpress

Expression data from the liver of wild-type and Cnot3+/- mice: Fed vs Fasted

2011-12-09 | GSE18925 | GEO

Expression data from mouse embryonic fibroblasts

Project description:In addition to transcriptional regulation, mRNA degradation critically contributes to gene expression as shown by various biological analysis. The CCR4-NOT complex serves as a major deadenylase that initiates mRNA degradation. We used microarrays to identify CCR4-NOT targets by searching for genes specifically stablized in the absence of CNOT3, a core subunit of the CCR4-NOT complex. Primary mouse embryonic fibroblasts (MEFs) were used for RNA extraction and hybridization on Affymetrix microarrays. CNOT3-knockdown MEFs were generated by Cre-mediated somatic recombination. We treated both control and CNOT-knockdown (CNOT3KD) MEFs with a transcriptional inhibitor, actinomycin D to focus on a stability of mRNAs.

2015-09-01 | E-GEOD-67418 | biostudies-arrayexpress

RNA-seq of mouse islets from Ins1-cre driven Cnot3 KO and control islets

Project description:The CCR4-NOT dedadenylase complex is essential for mRNA decay and various biological events.To understand roles of the complex in pancreatic beta cells, we compared global gene expression in Ins1-cre driven Cnot3 KO and control islets. Cnot3 is an important subunit of the complex and its knockout affects the complex activity.

2020-08-29 | E-MTAB-8729 | biostudies-arrayexpress

Regulation of B cell early development by CNOT3

2015-07-23 | GSE64455 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data