Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution
Abstract Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Resztak, Justyna A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2021.09.30.462672 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI032705107 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI032705107 | ||
| 003 | DE-627 | ||
| 005 | 20240425104503.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 211003s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2021.09.30.462672 |2 doi | |
| 035 | |a (DE-627)XBI032705107 | ||
| 035 | |a (biorXiv)10.1101/2021.09.30.462672 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Resztak, Justyna A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Genetic control of the dynamic transcriptional response to immune stimuli and glucocorticoids at single cell resolution |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Synthetic glucocorticoids, such as dexamethasone, have been used as treatment for many immune conditions, such as asthma and more recently severe COVID-19. Single cell data can capture more fine-grained details on transcriptional variability and dynamics to gain a better understanding of the molecular underpinnings of inter-individual variation in drug response. Here, we used single cell RNA-seq to study the dynamics of the transcriptional response to glucocorticoids in activated Peripheral Blood Mononuclear Cells from 96 African American children. We employed novel statistical approaches to calculate a mean-independent measure of gene expression variability and a measure of transcriptional response pseudotime. Using these approaches, we demonstrated that glucocorticoids reverse the effects of immune stimulation on both gene expression mean and variability. Our novel measure of gene expression response dynamics, based on the diagonal linear discriminant analysis, separated individual cells by response status on the basis of their transcriptional profiles and allowed us to identify different dynamic patterns of gene expression along the response pseudotime. We identified genetic variants regulating gene expression mean and variability, including treatment-specific effects, and demonstrated widespread genetic regulation of the transcriptional dynamics of the gene expression response. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Wei, Julong |e verfasserin |4 aut | |
| 700 | 1 | |a Zilioli, Samuele |e verfasserin |4 aut | |
| 700 | 1 | |a Sendler, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Alazizi, Adnan |e verfasserin |4 aut | |
| 700 | 1 | |a Mair-Meijers, Henriette E |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Peijun |e verfasserin |4 aut | |
| 700 | 1 | |a Wen, Xiaoquan |e verfasserin |0 (orcid)0000-0001-8990-2737 |4 aut | |
| 700 | 1 | |a Slatcher, Richard B |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Luca, Francesca |e verfasserin |0 (orcid)0000-0001-8252-9052 |4 aut | |
| 700 | 1 | |a Pique-Regi, Roger |e verfasserin |0 (orcid)0000-0002-1262-2275 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 23. Apr. |
| 773 | 1 | 8 | |g year:2024 |g day:23 |g month:04 |
| 856 | 4 | 0 | |u https://doi.org/10.1101/gr.276765.122 |x 0 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2021.09.30.462672 |x 0 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 23 |c 04 | ||