CHD7 promotes anti-viral short-lived effector CD8+ T cells
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ABSTRACT:
PROVIDER: PRJNA1147731 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30228200_1.fastq.gz | Fastqsanger.gz | |||
| SRR30228200_2.fastq.gz | Fastqsanger.gz | |||
| SRR30228201_1.fastq.gz | Fastqsanger.gz | |||
| SRR30228201_2.fastq.gz | Fastqsanger.gz | |||
| SRR30228202_1.fastq.gz | Fastqsanger.gz |
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Project description:CD8+ T cells differentiate into two subpopulations in response to acute viral infection: memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). MPECs and SLECs are epigenetically distinct; however, the epigenetic regulators required for formation of these subpopulations are mostly unknown. Here we performed an in vivo CRISPR screen in murine naive CD8+ T cells to identify the epigenetic regulators required for MPEC and SLEC formation, using the acute lymphocytic choriomeningitis virus (LCMV) Armstrong infection model. We identified the ATP-dependent chromatin remodeler chromodomain-helicase-DNA-binding-protein-7 (CHD7) as a positive regulator of SLEC formation, as knockout (KO) of Chd7 reduced SLECs numerically. In contrast, KO of Chd7 increased the formation of central memory T cells following pathogen clearance yet attenuated memory cell expansion following a rechallenge. These findings establish CHD7 as a novel positive regulator of SLEC and negative regulator of central memory T cell formation.
2024-09-23 | GSE274735 | GEO
Project description:CD8+ T cells differentiate into two subpopulations in response to acute viral infection: memory precursor effector cells (MPECs) and short-lived effector cells (SLECs). MPECs and SLECs are epigenetically distinct; however, the epigenetic regulators required for formation of these subpopulations are mostly unknown. Here we performed an in vivo CRISPR screen in murine naive CD8+ T cells to identify the epigenetic regulators required for MPEC and SLEC formation, using the acute lymphocytic choriomeningitis virus (LCMV) Armstrong infection model. We identified the ATP-dependent chromatin remodeler chromodomain-helicase-DNA-binding-protein-7 (CHD7) as a positive regulator of SLEC formation, as knockout (KO) of Chd7 reduced SLECs numerically. In contrast, KO of Chd7 increased the formation of central memory T cells following pathogen clearance yet attenuated memory cell expansion following a rechallenge. These findings establish CHD7 as a novel positive regulator of SLEC and negative regulator of central memory T cell formation.
2024-09-23 | GSE274736 | GEO
Project description:CHD7 promotes anti-viral short-lived effector CD8+ T cells [RNA-seq]
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Project description:CD8 effector T cells with a CD127hi KLRG1- phenotype are considered precursors to the long-lived memory pool, while KLRG1+ CD127low cells are viewed as short-lived effectors. Nevertheless, we and others have shown that a KLRG1+ CD127low population persists into the memory phase and that these T cells (termed long-lived effector cells or LLEC) display robust protective function during acute re-challenge with bacteria or viruses. Whether these T cells represent a true memory population or are instead a remnant effector cell population that failed to undergo initial contraction has remained unclear. Here, we show that LLEC from mice express a distinct phenotypic and transcriptional signature that shares characteristics of both early effectors and long-lived memory cells. Furthermore, we find that LLEC are exclusively derived from day 12 KLRG1+ effector cells. Our work challenges the concept that the KLRG1+ CD127low population is dominated by short-lived cells and shows that KLRG1 downregulation is not a prerequisite to become a long-lived protective memory T cell.
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Project description:Rapid protein degradation enables cells to quickly modulate protein abundance in response to stimuli. Previous studies have generally sought to delineate basic features of proteome turnover. A focused map of short-lived proteins, however, remains a missing piece of the human proteome. To begin to address this, we combined cycloheximide chase assays with advanced high-throughput quantitative proteomics to map short-lived proteins in four genetically distinct human cell lines. Apparent half-lives of ≤ 8 hr were measured for 1,017 proteins. Systematic analyses revealed general properties of short-lived proteins (e.g., enriched in substrate recognition subunits of E3 ubiquitin ligase complexes, thermally instable, evolutionarily younger). We further quantified 103 proteins with widely different stabilities among cell lines. Of these, we show that truncated forms of ATRX and GMDS were expressed in U2OS and HCT116 cells, respectively, which had shorter half-lives than their full-length counterparts. This study provides a large-scale resource of human short-lived proteins in cultured cells, leading to untapped avenues of protein regulation for therapeutic intervention.
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Project description:Targeted proTargeted protein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader. tein degradation has recently emerged as a novel option in drug discovery. Natural protein half-life is expected to affect the efficacy of degrading agents, but it has not been systematically explored to what extent it influences target protein degradation. Using mathematical modelling of protein degradation, we demonstrate that the natural half-life of a target protein has a dramatic effect on the level of protein degradation induced by a PROTAC which can pose significant hurdles to screening efforts. Moreover, we show that upon screening for degraders of short-lived proteins, agents that stall protein synthesis, such as GSPT1 degraders and generally cytotoxic compounds, deceptively appear as protein degrading agents. This is exemplified by the disappearance of short-lived proteins such as MCL1 and MDM2 upon GSPT1 degradation and upon treatment with cytotoxic agents such as doxorubicin. These findings have implications for target selection as well as for the type of control experiments required before concluding that a novel agent works as a bone-fide targeted protein degrader.
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