A missense mutation in AIOLOS causes B cell deficiency by interfering with IKAROS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523246 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8592480.fastq.gz | Fastqsanger.gz | |||
| SRR8592490.fastq.gz | Fastqsanger.gz | |||
| SRR8592500.fastq.gz | Fastqsanger.gz | |||
| SRR8592481.fastq.gz | Fastqsanger.gz | |||
| SRR8592491.fastq.gz | Fastqsanger.gz |
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Project description:A missense mutation (G158R) in Ikzf3 gene resulted in defective generation of B cells in mice. Pre-B cells were profoundly decreased in homozygous mutant mice. Heterozygous mutant mice showed milder B cell developmental defects, and decreased B cells in the secondary lymphoid organs were observed. Ikzf3 encodes Aiolos, which makes heterodimer with Ikaros. Our findings indicate that the loss-of-function mutation in Aiolos hinders B cell development by interfering Ikaros' function via formation of heterodimers.
2022-02-16 | GSE126778 | GEO
Project description:A missense mutation (G158R) in Aiolos, encoded by Ikzf3 gene, resulted in defective generation of B cells in mice. Pre-B cells were profoundly decreased in homozygous mutant mice. Heterozygous mutant mice showed milder B cell developmental defects, and B cells in the secondary lymphoid organs decreased. Genome-wide binding of Aiolos and Ikaros were altered in the thymus of homozygous Ikzf3 G158R mice. Our findings indicate that Aiolos-G158R hinders B cell development by interfering Ikaros' function via formation of heterodimers. A heterozygous missense variant (G159R) in AIOLOS, encoded by IKZF3 gene, resulted in impaired adaptive immunity, which predominantly manifested as profound B cell developmental defect. Genome-wide binding of wild-type AIOLOS and AIOLOS G159R mutant were examined in IKZF3 knock-out human pre-B cell line NALM-6, retrovirally transduced with doxycycline inducible wild-type AIOLOS or AIOLOS G159R. Changes in genome-wide binding and binding motif were observed for AIOLOS G159R mutant.
2021-05-01 | GSE167487 | GEO
Project description:A Variant in Human AIOLOS Impairs Adaptive Immunity by Interfering with IKAROS
| PRJNA704728 | ENA
Project description:Purpose: Cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex CRL4CRBN, is the target of the small molecules lenalidomide (Len) and avadomide (Ava). Upon binding of the drugs, Aiolos and Ikaros are recruited to the E3 ligase, ubiquitylated and subsequently degraded. In DLBCL cells, Aiolos and Ikaros are direct transcriptional repressors of interferon stimulated genes (ISG) and degradation of these substrates results in increased ISG protein levels resulting in decreased proliferation and apoptosis. Herein, we aimed to uncover the mechanism(s) Aiolos and Ikaros use to repress ISG transcription and provide a mechanistic rationale for a combination strategy enhance cell autonomous activites of CELMoDs. Results: We describe that in DLBCL, the repression of ISG transcription is accomplished in part through recruitment of large transcriptional complexes such as the nucleosome remodeling and deacetylase (NuRD) which modify the chromatin landscape of these promoters. A rational combination approach of Ava with a specific HDAC inhibitor leads to a significant increase in ISG transcription compared to either single agent, and synergistic antiproliferative activity in DLBCL cell lines. Conclusion: Our results provide a novel role for lineage factors Aiolos and Ikaros in DLBCL as well as further insight into the mechanism(s) of Aiolos and Ikaros mediated transcriptional repression and unique therapeutic combination strategies.
2022-07-12 | GSE201324 | GEO
Project description:Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1 and IKZF3 in human MM cell lines to gain further insight into their downstream gene regulatory networks. Our findings strongly support the central role of Ikaros and Aiolos in the action of the IMiDs. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment.
2018-09-12 | GSE113031 | GEO
Project description:Early B-lymphopoiesis depends on E2A, Ebf1, Pax5 and Ikaros family members. Here, we used acute protein degradation in vivo to identify direct target genes of these transcription factors in pro-B, small pre-B and immature B-cells. E2A, Ebf1 and Pax5 predominantly function as transcriptional activators by inducing open chromatin at their target genes, have largely unique functions and maintain cell viability in vivo by activating Bcl2l1. Ikaros and Aiolos cooperatively control early B-cell development and act as dedicated repressors to suppress open chromatin at their target genes. The surrogate light-chain genes Igll1 and Vpreb1 are directly activated by Ebf1 and Pax5 in pro-B cells and directly repressed by Ikaros and Aiolos in small pre-B cells. Pax5 and E2A contribute to V(D)J recombination by activating Rag1, Rag2, Dntt, Irf4 and Irf8. Like Pax5, Ebf1 also represses the cohesin-release factor gene Wapl to mediate prolonged loop extrusion across the Igh locus. In summary, in vivo protein degradation has provided unprecedented insight into the control of early B-lymphopoiesis by five transcription factors.
2024-06-21 | GSE259358 | GEO
Project description:Early B-lymphopoiesis depends on E2A, Ebf1, Pax5 and Ikaros family members. Here, we used acute protein degradation in vivo to identify direct target genes of these transcription factors in pro-B, small pre-B and immature B-cells. E2A, Ebf1 and Pax5 predominantly function as transcriptional activators by inducing open chromatin at their target genes, have largely unique functions and maintain cell viability in vivo by activating Bcl2l1. Ikaros and Aiolos cooperatively control early B-cell development and act as dedicated repressors to suppress open chromatin at their target genes. The surrogate light-chain genes Igll1 and Vpreb1 are directly activated by Ebf1 and Pax5 in pro-B cells and directly repressed by Ikaros and Aiolos in small pre-B cells. Pax5 and E2A contribute to V(D)J recombination by activating Rag1, Rag2, Dntt, Irf4 and Irf8. Like Pax5, Ebf1 also represses the cohesin-release factor gene Wapl to mediate prolonged loop extrusion across the Igh locus. In summary, in vivo protein degradation has provided unprecedented insight into the control of early B-lymphopoiesis by five transcription factors.
2024-06-21 | GSE259355 | GEO
Project description:Early B-lymphopoiesis depends on E2A, Ebf1, Pax5 and Ikaros family members. Here, we used acute protein degradation in vivo to identify direct target genes of these transcription factors in pro-B, small pre-B and immature B-cells. E2A, Ebf1 and Pax5 predominantly function as transcriptional activators by inducing open chromatin at their target genes, have largely unique functions and maintain cell viability in vivo by activating Bcl2l1. Ikaros and Aiolos cooperatively control early B-cell development and act as dedicated repressors to suppress open chromatin at their target genes. The surrogate light-chain genes Igll1 and Vpreb1 are directly activated by Ebf1 and Pax5 in pro-B cells and directly repressed by Ikaros and Aiolos in small pre-B cells. Pax5 and E2A contribute to V(D)J recombination by activating Rag1, Rag2, Dntt, Irf4 and Irf8. Like Pax5, Ebf1 also represses the cohesin-release factor gene Wapl to mediate prolonged loop extrusion across the Igh locus. In summary, in vivo protein degradation has provided unprecedented insight into the control of early B-lymphopoiesis by five transcription factors.
2024-06-21 | GSE260522 | GEO
Project description:In the present study, we report a human-inherited, impaired, adaptive immunity disorder, which predominantly manifested as a B cell differentiation defect, caused by a heterozygous IKZF3 missense variant, resulting in a glycine-to-arginine replacement within the DNA-binding domain of the encoded AIOLOS protein. Using mice that bear the corresponding variant and recapitulate the B and T cell phenotypes, we show that the mutant AIOLOS homodimers and AIOLOS-IKAROS heterodimers did not bind the canonical AIOLOS-IKAROS DNA sequence. In addition, homodimers and heterodimers containing one mutant AIOLOS bound to genomic regions lacking both canonical motifs. However, the removal of the dimerization capacity from mutant AIOLOS restored B cell development. Hence, the adaptive immunity defect is caused by the AIOLOS variant hijacking IKAROS function. Heterodimeric interference is a new mechanism of autosomal dominance that causes inborn errors of immunity by impairing protein function via the mutation of its heterodimeric partner.
| S-EPMC8958960 | biostudies-literature
Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.
2023-10-20 | GSE220028 | GEO