Tissue-specific modifier alleles determine Mertk loss-of-function traits
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ABSTRACT:
PROVIDER: PRJNA843677 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19445736_1.fastq.gz | Fastqsanger.gz | |||
| SRR19445736_2.fastq.gz | Fastqsanger.gz | |||
| SRR19445737_1.fastq.gz | Fastqsanger.gz | |||
| SRR19445737_2.fastq.gz | Fastqsanger.gz | |||
| SRR19445738_1.fastq.gz | Fastqsanger.gz |
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Project description:Tolerogenic dendritic cells (tol-DCs) offer a promising therapeutic potential for autoimmune diseases. Tol-DCs have been reported to inhibit immunogenic responses, yet little is known about the mechanisms controlling their tolerogenic status, as well as associated specific markers. Here we show that the anti-inflammatory TAM receptor tyrosine kinase MERTK, is highly expressed on clinical grade dexamethasone-induced human tol-DCs and mediates their tolerogenic effect. Neutralization of MERTK in allogenic mixed lymphocyte reactions as well as autologous DC-T cell cultures leads to increased T cell proliferation and IFN-g production. Additionally, we identify a previously unrecognized non-cell autonomous regulatory function of MERTK expressed on DCs. Recombinant Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK agonist Protein S (PROS1) expressed by T cells. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine pro-proliferative mechanism. Collectively, these results suggest that MERTK on tol-DCs directly inhibits T cell activation through the competition for PROS1 interaction with MERTK in the T cells. Targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy. The complete database comprised the expression measurements of 54,675 genes for: immature (n=9), mature (n=7) and tolerogenic (n=8). Influence of treatment with dexamethasone (n=3) and LPS (n=2) are included.
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Project description:Whole transcriptome RNA-seq analysis to measure group-wise RNA expression level of the MERTK gene in 3 healthy controls (known to be homozygous non-risk haplotype at MERTK gene locus) and to compare this to the group-wise RNA expression level of the MERTK gene in 5 Multiple Sclerosis-affected (MS-affected) individuals (known to be homozygous for the MS risk haplotype at the MERTK gene locus). We sequenced the whole transcriptome of 3 healthy control samples which were all homozygous for the MS non-risk haplotype at the MERTK gene. We also did the same RNA-seq protocol on 5 MS-affected subjects that were all homozygous for the Risk haplotype at the MERTK gene. All 8 samples were sequenced evenly across 3 lanes of an Illumina HiSeq NGS machine to remove any batch-type effects that could be caused by sequencing e.g. all cases in one lane and all controls in another lane.
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Project description:Tolerogenic dendritic cells (tol-DCs) offer a promising therapeutic potential for autoimmune diseases. Tol-DCs have been reported to inhibit immunogenic responses, yet little is known about the mechanisms controlling their tolerogenic status, as well as associated specific markers. Here we show that the anti-inflammatory TAM receptor tyrosine kinase MERTK, is highly expressed on clinical grade dexamethasone-induced human tol-DCs and mediates their tolerogenic effect. Neutralization of MERTK in allogenic mixed lymphocyte reactions as well as autologous DC-T cell cultures leads to increased T cell proliferation and IFN-g production. Additionally, we identify a previously unrecognized non-cell autonomous regulatory function of MERTK expressed on DCs. Recombinant Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK agonist Protein S (PROS1) expressed by T cells. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine pro-proliferative mechanism. Collectively, these results suggest that MERTK on tol-DCs directly inhibits T cell activation through the competition for PROS1 interaction with MERTK in the T cells. Targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy.
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Project description:Purpose: The goal of this study is to characterize the the different CNS cell types in the mouse corpus callosum over three different cuprizone treatment timepoints - (Baseline, 4 weeks, 4 weeks + 3 weeks of recovery) and compare the Mertk-WT vs Mertk-KO response to demyelination. Methods: 3-4 biological replicates (mice) were used for each timepoint/genotype. Tissues were dissociated into single cells for preparation of 10X libraries and sequenced with HiSeq 2500 (Illumina). Results: scRNA-Seq data were analyzed with an in-house analysis pipeline. Briefly, reads were demultiplexed based on perfect matches to expected cell barcodes. Transcript reads were aligned to the mouse reference genome (GRCm38) using GSNAP (Wu and Nacu, 2010). Only uniquely mapping reads were considered for downstream analysis. Transcript counts for a given gene were based on the number of unique molecular identifiers (UMIs) for reads overlapping exons in sense orientation. To account for sequencing or PCR errors, one mismatch was allowed when collapsing UMI sequences. Cell barcodes from empty droplets were filtered by requiring a minimum number of detected transcripts. Cells with less than 1000 total UMIs were discarded. Conclusions: We show differences between Mertk-WT and Mertk-KO cellular profiles, particularly at the 4 week Cuprizone timepoint. In addition, our data show a distinct, yet heterogenous, population of oligodendrocytes that arise in the cuprizone model where remyelination is spontaneous and robust. Our results provide new insights into the cellular response to demyelination, that includes a resource for comparing and interpreting neurodegenerative disease models.
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