GEO series
Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells [CRISPRi]
Summary
Cis-regulatory elements (CRE) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of adjacent T cell costimulatory genes CD28, CTLA4, and ICOS encoding regulators of cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells – both Conventional and Regulatory subsets – uncovered gene-, cell subset- and stimulation-specific CREs. Integrating these data with CRISPR knockout (KO) screens and ATAC-seq characterization identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. Lastly, we discovered and extensively validated a critical CTCF boundary that governs this locus, serving to reinforce CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.
Published in
Mowery CT, Freimer JW, Chen Z et al.
· Nature genetics 2024
· PMID 38811842
· doi:10.1038/s41588-024-01743-5
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE261330_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 28 samples.
Also filed as BioProject PRJNA1086507. Searching any of these in the dataset finder brings you back here.
Study design
28 conditions, each sampled once — no replicated groups
Read from 28 sample titles: 28 distinct titles with little repetition. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8140625 Donor 1 Treg, Resting, CTLA4-High
- GSM8140626 Donor 1 Treg, Resting, CTLA4-Low
- GSM8140627 Donor 1 Treg, 6 hour Restimulation, CTLA4-High
- GSM8140628 Donor 1 Treg, 6 hour Restimulation, CTLA4-Low
- GSM8140629 Donor 2 Treg, Resting, CTLA4-High
- GSM8140630 Donor 2 Treg, Resting, CTLA4-Low
- GSM8140631 Donor 2 Treg, 6 hour Restimulation, CTLA4-High
- GSM8140632 Donor 2 Treg, 6 hour Restimulation, CTLA4-Low
- GSM8140633 Donor 1 Treg, Resting, CD28-Low
- GSM8140634 Donor 1 Treg, Resting, CD28-High
- GSM8140635 Donor 2 Treg, Resting, CD28-Low
- GSM8140636 Donor 2 Treg, Resting, CD28-High
- GSM8140637 Donor 1 Treg, 24 hour Restimulation, ICOS-Low
- GSM8140638 Donor 1 Treg, 24 hour Restimulation, CD28-High
- GSM8140639 Donor 2 Treg, 24 hour Restimulation, ICOS-Low
- GSM8140640 Donor 2 Treg, 24 hour Restimulation, CD28-High
- GSM8140641 Donor 1 Tconv, Resting, CD28-High
- GSM8140642 Donor 1 Tconv, Resting, CD28-Low
- GSM8140643 Donor 1 Tconv, 6 hour Restimulation, CTLA4-High
- GSM8140644 Donor 1 Tconv, 6 hour Restimulation, CTLA4-Low
- GSM8140645 Donor 1 Tconv, 24 hour Restimulation, ICOS-High
- GSM8140646 Donor 1 Tconv, 24 hour Restimulation, ICOS-Low
- GSM8140647 Donor 2 Tconv, Resting, CD28-High
- GSM8140648 Donor 2 Tconv, Resting, CD28-Low
- GSM8140649 Donor 2 Tconv, 6 hour Restimulation, CTLA4-High
- GSM8140650 Donor 2 Tconv, 6 hour Restimulation, CTLA4-Low
- GSM8140651 Donor 2 Tconv, 24 hour Restimulation, ICOS-High
- GSM8140652 Donor 2 Tconv, 24 hour Restimulation, ICOS-Low
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