 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Jan 31, 2024 |
| Title |
Chromatin Binding Deubiquitinase MYSM1 in Dendritic Cell Development and Activation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Dendritic cells (DCs) are the most significant antigen presenting cells of the immune system, critical for the activation of naïve T cells. The pathways controlling DC development, maturation, and effector function therefore require precise regulation to allow for an effective induction of adaptive immune response. MYSM1 is a chromatin binding deubiquitinase (DUB), known to act as an activator of gene expression via its catalytic activity for monoubiquitinated histone H2A (H2A-K119ub), which is a highly abundant repressive epigenetic mark. MYSM1 is an important regulator of hematopoiesis in mouse and human, and a systemic constitutive loss of Mysm1 in mice results in a depletion of many hematopoietic progenitors, including DC precursors, with the downstream loss of most DC lineage cells. However, the roles of MYSM1 at the later checkpoints in DC development, maturation, activation, and effector function at present remain unknown. In the current work, using a range of mouse models (Mysm1flCreERT2, Mysm1flCD11c-cre, Mysm1DN), we further the understanding of MYSM1 functions in the DC lineage: assessing the requirement for MYSM1 in DC development independently of other complex developmental phenotypes, exploring its role at the later checkpoints in DC maintenance and activation in response to microbial stimulation, and testing the requirement for the DUB catalytic activity of MYSM1 in these processes. Surprisingly, we demonstrate that MYSM1 expression and catalytic activity in DCs are dispensable for the maintenance of DC numbers in vivo or for DC activation in response to microbial stimulation. In contrast, MYSM1 and its DUB catalytic activity in hematopoietic progenitors are essential for normal DC development, and its loss results not only in a severe depletion of DC lineage cells, but also in the production of functionally altered DCs, with a dysregulation of many housekeeping transcriptional programs and significantly altered responses to microbial stimulation.
|
| |
|
| Overall design |
To further analyze the effects of a pan-hematopoietic loss of MYSM1 function on DC responses to microbial stimulation, bulk RNA-seq of BMDCs was carried out using BMDCs derived from tamoxifen treated CreERT2 transgenic mice of Mysm1fl/DN and control Mysm1fl/+ genotypes, at steady-state and following LPS stimulation.
To be more specific, tamoxifen treated CreERT2Mysm1fl/DN mice (Δ/DN, group C) express a catalytically inactive MYSM1, whereas CreERT2Mysm1fl/+ control mice (Δ/+, group A) express wild type MYSM1. Bone marrow was extracted at >12 weeks after the tamoxifen treatment, BMDCs derived in vitro over 9 days of culture, and subsequently harvested and cultured for further 18 hours either untreated (US) or with LPS stimulation (10 ng/mL). The samples (US Δ/DN, LPS Δ/DN, US Δ/+, LPS Δ/+) were send to Institut de recherches cliniques de Montréal (IRCM) for RNA-Seq gene expression profilling.
|
| Web link |
https://pubmed.ncbi.nlm.nih.gov/38316548/
|
| |
|
| Contributor(s) |
Mousa M, Liang Y, Tung L, Wang H, Langlais D, Krawczyk C, Nijnik A |
| Citation(s) |
38316548 |
| |
| Submission date |
Jul 05, 2023 |
| Last update date |
May 01, 2024 |
| Contact name |
Anastasia Nijnik |
| E-mail(s) |
[email protected]
|
| Phone |
514-398-5567
|
| Organization name |
McGill University
|
| Department |
Physiology
|
| Lab |
Nijnik Lab
|
| Street address |
Rm 368 - 3649 Promenade Sir William Osler
|
| City |
Montreal |
| State/province |
Quebec |
| ZIP/Postal code |
H3G 0B1 |
| Country |
Canada |
| |
|
| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
|
| Samples (15)
|
|
| Relations |
| BioProject |
PRJNA991539 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE236534_RAW.tar |
5.3 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
|
|
|
|
 |
Less...
More...