Histone marks identify novel transcription factors that parse CAR-T cell subset-of-origin, clinical potential and expansion [RNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1071987 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27830231_1.fastq.gz | Fastqsanger.gz | |||
| SRR27830231_2.fastq.gz | Fastqsanger.gz | |||
| SRR27830232_1.fastq.gz | Fastqsanger.gz | |||
| SRR27830232_2.fastq.gz | Fastqsanger.gz | |||
| SRR27830233_1.fastq.gz | Fastqsanger.gz |
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Project description:Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionized the treatment of blood cancers. Parsing the genetic underpinnings of T cell precursor quality and subsequent CAR-T efficacy is challenging. RNA-seq informs infused CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasizes effector and metabolism genes. We investigated whether analyses of transcriptionally repressive and permissive histone methylation marks reveal associations with CAR-T potential beyond what is seen by transcriptomic analysis. We assessed human CD8+ T cell naïve, central and effector memory subsets that form the substrate of CAR-T cell products, and CAR-T cells derived from these subsets. We extended these observations into the clinic, by examining CAR-T products from a clinical trial of lymphoma patients (NCT01865617). We report that histone marks provide a rich dataset for identification of genes not apparent by conventional transcriptomics. Histone marks improved identification of T cell subsets, CAR-T manufactured from these subsets, and CAR-T manufactured from central memory cells from healthy donors and patients. Using this discriminative approach, we controlled for clinical factors and identified a factor, KLF7, associated with CAR-T cell expansion in patients. Epigenomic methods are an orthogonal, robust and wide-reaching approach for the assessment of T cell immunotherapeutic quality.
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Project description:Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionized the treatment of blood cancers. Parsing the genetic underpinnings of T cell precursor quality and subsequent CAR-T efficacy is challenging. RNA-seq informs infused CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasizes effector and metabolism genes. We investigated whether analyses of transcriptionally repressive and permissive histone methylation marks reveal associations with CAR-T potential beyond what is seen by transcriptomic analysis. We assessed human CD8+ T cell naïve, central and effector memory subsets that form the substrate of CAR-T cell products, and CAR-T cells derived from these subsets. We extended these observations into the clinic, by examining CAR-T products from a clinical trial of lymphoma patients (NCT01865617). We report that histone marks provide a rich dataset for identification of genes not apparent by conventional transcriptomics. Histone marks improved identification of T cell subsets, CAR-T manufactured from these subsets, and CAR-T manufactured from central memory cells from healthy donors and patients. Using this discriminative approach, we controlled for clinical factors and identified a factor, KLF7, associated with CAR-T cell expansion in patients. Epigenomic methods are an orthogonal, robust and wide-reaching approach for the assessment of T cell immunotherapeutic quality.
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Project description:Histone marks identify novel transcription factors that parse CAR-T cell subset-of-origin, clinical potential and expansion [CUT&RUN]
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Project description:Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production. In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics.
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Project description:This SuperSeries is composed of the SubSeries listed below. This dataset is part of a larger study, entitled “Widespread epigenetic changes to the enhancer landscape of mouse liver induced by a specific xenobiotic agonist ligand of the nuclear receptor CAR”, which found that active enhancer and promoter histone marks induced by TCPOBOP were enriched at opening DNase hypersensitive sites (DHS) and TCPOBOP-inducible genes. Enrichment of CAR binding and CAR motifs was seen at opening DHS and their inducible drug/lipid metabolism gene targets, and at many constitutively open DHS located nearby. TCPOBOP-responsive cell cycle and DNA replication genes co-dependent on MET/EGFR signaling for induction were also enriched for CAR binding. A subset of opening DHS and many closing DHS mapping to TCPOBOP-responsive target genes did not bind CAR, indicating an indirect mechanism for their changes in chromatin accessibility. TCPOBOP-responsive DHS were also enriched for induced binding of RXRA, CEBPA and CEBPB, and for motifs for liver-enriched factors that may contribute to liver-specific transcriptional responses to TCPOBOP exposure. These studies elucidate the enhancer landscape of TCPOBOP-exposed liver and the widespread epigenetic changes that are induced by both direct and indirect mechanisms linked to CAR activation.
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Project description:Chromatin immunoprecipitation and sequencing for the H3K27me3 histone mark was performed on livers of male mice either treated with vehicle or with TCPOBOP for 27 h. This dataset is part of a larger study, entitled “Widespread epigenetic changes to the enhancer landscape of mouse liver induced by a specific xenobiotic agonist ligand of the nuclear receptor CAR”, which found that active enhancer and promoter histone marks induced by TCPOBOP were enriched at opening DNase hypersensitive sites (DHS) and TCPOBOP-inducible genes. Enrichment of CAR binding and CAR motifs was seen at opening DHS and their inducible drug/lipid metabolism gene targets, and at many constitutively open DHS located nearby. TCPOBOP-responsive cell cycle and DNA replication genes co-dependent on MET/EGFR signaling for induction were also enriched for CAR binding. A subset of opening DHS and many closing DHS mapping to TCPOBOP-responsive target genes did not bind CAR, indicating an indirect mechanism for their changes in chromatin accessibility. TCPOBOP-responsive DHS were also enriched for induced binding of RXRA, CEBPA and CEBPB, and for motifs for liver-enriched factors that may contribute to liver-specific transcriptional responses to TCPOBOP exposure. These studies elucidate the enhancer landscape of TCPOBOP-exposed liver and the widespread epigenetic changes that are induced by both direct and indirect mechanisms linked to CAR activation.
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