Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA354784 | ENA |
REPOSITORIES: ENA
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Project description: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.
2017-03-15 | GSE90474 | GEO
Project description:Survey of major histocompatibility complex class II diversity in pig-tailed macaques
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Project description:The major histocompatibility complex class II (MHC II) is important for the adaptive immune response because it presents processed antigens to CD4-positive T-cells. Conventional chemotherapeutic agents (e.g., melphalan, adriamycin, hydroxyurea) induce tumor cell death by causing DNA double strand breaks (DSBs), which are crucial for anti-tumor effects. However, the cellular response induced at low doses of these agents that do not cause immediate cell death is unclear. We have employed microarray expression profiling to identify genes which are induced by low dose of chemotherapeutic agents. Multiple myeloma cell line KMS12PE was treated with vehicle, 2 μM melphalan, or 50 nM adriamycin. These agents transcriptionally induced the major histocompatibility complex class II (MHC II) genes. They also increased the expressions of MHC class II transactivator (CIITA), the master regulator of MHC II genes and interferon regulatory factor 1 (IRF1), a transcription factor for CIITA.
2021-03-19 | GSE151040 | GEO
Project description:Unravelling the architecture of Major Histocompatibility Complex class II haplotypes in rhesus macaques
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Project description:Unravelling the architecture of Major Histocompatibility Complex class II haplotypes in rhesus macaques
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Project description:Macaque Major Histocompatibility Complex Class I Full-Length Genomic Sequences
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Project description:mRNA degradation critically contributes to tissue development and function as well as transcription. The CCR4-NOT complex serves as a major deadenylase that initiates mRNA degradation. We used microarrays to identify deregulated genes in the white adipose tissues lacking CNOT3, a core subunit of the CCR4-NOT complex.
2017-01-01 | GSE86930 | GEO
Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189771 | GEO
Project description:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189772 | GEO