Effects on gene expression by Aff3-deficiency
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE193735 | GEO | 2023/01/14
REPOSITORIES: GEO
Similar Datasets
Project description:Effects on gene expression by Aff3-deficiency
| PRJNA797433 | ENA
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE246554 | GEO
Project description:We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with de novo variants in the AFF3 degron , a sequence involved in its binding to ubiquitin ligase. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. In line with this hypothesis, we describe an individual presenting a KINSSHIP-like phenotype carrying a partial duplication of AFF3. Further screening of intellectual disability cohorts revealed nine individuals with heterozygous and three with homozygous loss-of-function (LoF) variants, as well as two probands with compound LoF/missense and six with biallelic missense mutations in AFF3, who displayed a milder syndrome. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA confirming their association with the ablation of aff3. Conversely, the missense isoforms did not complement demonstrating the deleteriousness of the variants identified in affected individuals. To assess the different effect of these variants, we profiled the transcriptome of fibroblasts of affected individuals and isogenic cells harboring DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. While the same pathways are affected, only one-third of the differentially expressed genes are common to both homozygote datasets, indicating that AFF3 LoF and DN mutations largely modulate transcriptomes differently. In particular, the apical junction and DNA repair pathways displayed opposite modulation. Our results and the high pleiotropy shown by this locus in GWASes suggest that even slight changes in the AFF3 function might be deleterious.
2024-02-14 | GSE241621 | GEO
Project description:Genomic imprinting is an epigenetic regulation which leads to gene expression in a parent-of-origin specific manner. Previously we have demonstrated that AFF3, the central component of Super Elongation Complex-like 3 (SEC-L3), can specifically bind both the intergenic differentially methylated region (IG-DMR) and the enhancer within the imprinted Dlk1-Dio3 locus to regulate the expression of the Meg3 polycistron. However, the mechanism underlying how AFF3 can interact with distinct chromatin regulatory elements remains unknown. Here, we demonstrate that AFF3 is associated with the Krüppel-like zinc finger protein ZFP281. ZFP281 is required for the recruitment of AFF3 to the enhancer and regulates the allele-specific expression of the Meg3 polycistron in mouse embryonic stem (ES) cells at the transcriptional elongation level. Our genome-wide analyses further identify ZFP281 as a critical factor generally associating with AFF3 at enhancers and functioning together with AFF3 in regulating the expression of a subset of gene. Our study suggests that different zinc finger proteins can function as molecular switchers to regulate the context-dependent function of AFF3 and set a balanced chromatin state for maintaining the allele specific expression pattern of the imprinted Dlk1-Dio3 locus. PLEASE BE AWARE THAT THE SUBMITTER REQUESTED DELETION OF BIGWIG AND PEAK-CALL FILES POST-PUBLICATION. PLEASE CONTACT SUBMITTER FOR FURTHER INFORMATION.
2016-12-08 | GSE77115 | GEO
Project description:Naïve CD8 T cells must be maintained in a quiescent metabolic state in order to respond robustly to infection while avoiding inappropriate activation and causing immunopathology. With age this quiescent state is lost and the CD8 T cell response to infection decreases. The factors regulating metabolic quiescence of CD8 T cells and how this regulation is lost during aging are not completely understood. Herein, we identify the transcription factor AFF3 as a novel regulator of metabolic quiescence in naïve CD8 T cells. While naïve AFF3 deficient CD8 T cells are more metabolically active prior to infection, they have reduced accumulation in response to viral infection and this is correlated with a poor capacity to engage glycolysis. During aging in both murine and human CD8 T cells, AFF3 expression is reducing, correlating with to a loss of quiescent metabolism without the cells entering an activated state. Our data highlights the role of the metabolism in CD8 T cell quiescence and identifies a novel transcription factor that may be a target to reinvigorate CD8 T cell responses during aging.
2026-06-01 | GSE331107 | GEO
Project description:Mutation-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
| PRJNA1008999 | ENA
Project description:Mutation-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles
| PRJNA1033619 | ENA
Project description:Genomic imprinting is a critical developmental process characteristic of parent-of-origin- specific gene expression. Here, we have identified the AFF family protein, Aff3, as a factor that functionally interacts with imprinted loci. Indeed, our genome-wide studies demonstrate that Aff3 specifically binds both imprinting control regions (ICRs) and enhancers within imprinted loci in an allele-specific manner. We have identified the molecular regulators involved in the recruitment of Aff3 to ICRs to impede transcription through the ICR, and provide a mechanism requiring Aff3 within the Super Elongation Complex-like 3 (SEC-L3) in the expression of an imprinted polycistronic transcript spanning the Dlk1-Dio3 locus. Our study also shows that DNA methylation at the ICR reinforces silencing of its related enhancers by controlling the binding and activity of Aff3 in an allele-specific manner. This study provides molecular details about the regulation of dosage-critical imprinted gene expression through Aff3âs function in transcriptional elongation control. ChIP-seq of Aff3 in different mES cells. ChIP-seq of Aff3, PolII, H3K9me3 in uniparental MEF cell lines. ChIP-seq of H3K27ac and PolII in mES cells after Aff3 shRNA and non-targeting shRNA. ChIP-seq of H3K27ac in wild type and Zfp57 knockout ES cells. Total RNA-seq and nascent RNA-seq of mES cells after Aff3 shRNA and non-targeting shRNA. Total RNA-seq of uniparental MEF cells after Aff3 shRNA and non-targeting shRNA.
2016-07-03 | E-GEOD-64489 | biostudies-arrayexpress
Project description:Genomic imprinting is a critical developmental process characteristic of parent-of-origin- specific gene expression. Here, we have identified the AFF family protein, Aff3, as a factor that functionally interacts with imprinted loci. Indeed, our genome-wide studies demonstrate that Aff3 specifically binds both imprinting control regions (ICRs) and enhancers within imprinted loci in an allele-specific manner. We have identified the molecular regulators involved in the recruitment of Aff3 to ICRs to impede transcription through the ICR, and provide a mechanism requiring Aff3 within the Super Elongation Complex-like 3 (SEC-L3) in the expression of an imprinted polycistronic transcript spanning the Dlk1-Dio3 locus. Our study also shows that DNA methylation at the ICR reinforces silencing of its related enhancers by controlling the binding and activity of Aff3 in an allele-specific manner. This study provides molecular details about the regulation of dosage-critical imprinted gene expression through Aff3’s function in transcriptional elongation control.
2016-01-01 | GSE64489 | GEO