Cop1 wildtype and knockout ATAC-seq in BMDMs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA615357 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s disease (AD) pathogenesis has been a major advance. The precise mechanisms controlling pathogenic programs of microglia gene expression, however, remain poorly understood. The transcription factor (TF) c/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß is upregulated in AD. Despite mounting evidence that the levels of this pivotal pro-inflammatory TF are tightly regulated, how this is achieved is unclear as alterations in its amounts are not reflected in transcript levels. Remarkably, we find that this TF is primarily regulated post-translationally. Here we show that the ubiquitin ligase Cop1 functions as a “brake” on microglial activation by targeting c/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß protein rapidly and dramatically accumulates leading to engagement of a potent pro-inflammatory and ApoE gene-expression program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies revealed that the neurotoxicity was almost entirely attributable to complement. Unexpectedly, loss of a single allele of c/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
2020-08-14 | GSE147557 | GEO
Project description:Bone marrow was extracted from mice that are COP1-wt Rosa26-CreERT2 or COP1-floxed Rosa26-CreERT2 BMDMs were obtained by culturing bone marrow precursors in media containing 20% of supernatant from L929 cells. At day 4 of differentiation 4-OHT was added at 1uM to induce deletion of COP1 in BMDMs derived from COP1-floxed mice. At day 7 of differentiation, BMDMs were treated with 100 ng/ml of LPS or not. BMDMs were directly harvested in lysis buffer (from Qiagen RNeasy mini kit) at different time points (0h, 2.5h, 2.5h, 4h, 6h, 9h and 13h) following LPS stimulation. Three BMDMs preparations per group: G1: BMDMs from COP1-wt mice (expressing the wt allele of COP1) CRE positive. G2: BMDMs from COP1-floxed mice (expressing the floxed allele of COP1) CRE positive
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s disease (AD) pathogenesis has been a major advance. The precise mechanisms controlling pathogenic programs of microglia gene expression, however, remain poorly understood. The transcription factor (TF) c/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß is upregulated in AD. Despite mounting evidence that the levels of this pivotal pro-inflammatory TF are tightly regulated, how this is achieved is unclear as alterations in its amounts are not reflected in transcript levels. Remarkably, we find that this TF is primarily regulated post-translationally. Here we show that the ubiquitin ligase Cop1 functions as a “brake” on microglial activation by targeting c/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß protein rapidly and dramatically accumulates leading to engagement of a potent pro-inflammatory and ApoE gene-expression program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies revealed that the neurotoxicity was almost entirely attributable to complement. Unexpectedly, loss of a single allele of c/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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Project description:The realization in the last decade that dysregulated microglia are intimately involved in Alzheimer’s disease (AD) pathogenesis has been a major advance. The precise mechanisms controlling pathogenic programs of microglia gene expression, however, remain poorly understood. The transcription factor (TF) c/EBPß is highly expressed in microglia and is known to regulate expression of pro-inflammatory genes. Notably, c/EBPß is upregulated in AD. Despite mounting evidence that the levels of this pivotal pro-inflammatory TF are tightly regulated, how this is achieved is unclear as alterations in its amounts are not reflected in transcript levels. Remarkably, we find that this TF is primarily regulated post-translationally. Here we show that the ubiquitin ligase Cop1 functions as a “brake” on microglial activation by targeting c/EBPß for ubiquitination and subsequent proteasomal mediated degradation. In the absence of Cop1, c/EBPß protein rapidly and dramatically accumulates leading to engagement of a potent pro-inflammatory and ApoE gene-expression program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies revealed that the neurotoxicity was almost entirely attributable to complement. Unexpectedly, loss of a single allele of c/EBPß, rescued the pro-inflammatory phenotype underscoring a significant gene dosage effect. We also found that Cop1 deletion accelerated disease progression in a mouse model of tau-mediated neurodegeneration where elevated ApoE plays a deleterious role. Taken together these results point to c/EBPß as a potential therapeutic target for inflammation-driven neurodegeneration as the heterozygote animal is otherwise normal.
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