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Evolutionarily guided transcription factor design programs novel T cell states [bulkRNA-seq]

ABSTRACT: Evolutionarily guided transcription factor design programs novel T cell states [bulkRNA-seq]

PROVIDER: PRJNA1178726 | ENA |

REPOSITORIES: ENA

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Evolutionarily guided transcription factor design programs novel T cell states [bulkRNA-seq]

Project description:Protein-coding genes in the human genome evolved via modular rearrangement of domains from ancestral genes. Here, we develop a scalable, evolutionarily guided method to assemble novel protein-coding genes from constituent domains within a protein family, termed DESynR (Domain Engineered via Synthesis and Recombination) factors. Using primary human chimeric antigen receptor-T cells as a model system, we find that the expression of DESynR Activator Protein-1 (AP-1) transcription factors (TFs) significantly outperforms the expression of natural AP-1 TFs in multiple functional assays in vitro and in vivo. Top DESynR AP-1 TFs exhibit non-intuitive architectures of constituent domains, including from TFs that are not canonically expressed in T cells. DESynR AP-1 TFs induce broad transcriptional and epigenetic reprogramming of T cells and in some cases, lead to the development of non-natural T cell states, engaging gene modules from disparate human cell types. Taken together, we demonstrate that novel configurations of existing protein domains may uncover non-evolved genes that program cell states with therapeutically-relevant functions.

2024-11-26 | GSE280508 | GEO

Evolutionarily guided transcription factor design programs novel T cell states [scRNA-seq, MULTI-seq]

Project description:Evolutionarily guided transcription factor design programs novel T cell states [scRNA-seq, MULTI-seq]

| PRJNA1178725 | ENA

Evolutionarily guided transcription factor design programs novel T cell states [scRNA-seq, MULTI-seq]

2024-11-26 | GSE280509 | GEO

Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design

Project description:An Adeno-Associated Virus capsid fitness landscape reveals a frameshifted viral gene and in vivo design principles, enabling machine-guided engineering.

2019-11-29 | GSE139657 | GEO

A computer-guided design tool to increase the efficiency of cellular conversions

Project description:A computer-guided design tool to increase the efficiency of cellular conversions

| PRJNA698774 | ENA

A computer-guided design tool to increase the efficiency of cellular conversions

Project description:Here we introduce a computer-guided design tool that combines a computational framework for prioritizing more efficient combinations of instructive factors (IFs) of cellular conversions, called IRENE, with a transposon-based genomic integration system for efficient delivery. Particularly, IRENE relies on a stochastic gene regulatory network model that systematically prioritizes more efficient IFs by maximizing the agreement of the transcriptional and epigenetic landscapes between the converted and target cells. Our predictions substantially increased the efficiency of two established iPSC-differentiation protocols (natural killer cells and melanocytes) and established the first protocol for iPSC-derived mammary epithelial cells with high efficiency.

2021-02-02 | GSE165961 | GEO

Evolutionarily conserved sequence motif analysis guided development of chemically defined hydrogels for therapeutic angiogenesis

Project description:Evolutionarily conserved sequence motif analysis guided development of chemically defined hydrogels for therapeutic angiogenesis

| PRJNA523037 | ENA

Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design

Project description:Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design

| PRJNA586835 | ENA

Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

Project description:Structure-guided design of a selective inhibitor of the methyltransferase KMT9 with cellular activity

| PRJNA986527 | ENA

Warehouse-based, immunopeptidome-guided design of personalised peptide vaccines shows feasibility in clinical trial evaluation in CLL patients

Project description:Cancer peptide vaccination represents a promising therapeutic approach, but has been hampered by lack of suitable antigens and restricted applicability due to different HLA backgrounds of individual patients. We here introduce a novel warehouse-based concept for composition of personalized peptide vaccines and report on its successful application in a Phase II clinical trial in patients with chronic lymphocytic leukemia (CLL) after first-line therapy. 26 CLL patients in at least partial remission (PR) after 6 months of immuno-chemotherapy were vaccinated with a personalized vaccine compiled from a premanufactured peptide warehouse comprising immunopeptidome-defined CLL-associated peptides. Primary objective was evaluation of immunogenicity, secondary objectives were safety and minimal residual disease (MRD) response. Immunopeptidome-guided vaccine composition was throughout successful, proving the feasibility of warehouse-based vaccine design. Vaccination was well tolerated, with local injection site reactions being the most common adverse event. Only few patients showed vaccine-induced T cell responses, attributable to their inability to mount strong immune responses due to immunechemotherapy and lack of potent adjuvant formulations. Both issues are addressed within a follow-up trial (NCT04688385), combining the immunopeptidome-guided warehouse-based vaccine design reported here with a potent novel adjuvant evaluating personalized multi- peptide vaccination in CLL patients under T cell supportive BTK inhibitor therapies.

2024-11-08 | PXD054248 | Pride

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