Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity
Quantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes fo...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/68203 |
| _version_ | 1811227938248458240 |
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| author | Brian Ritchey Qimin Hai Juying Han John Barnard Jonathan D Smith |
| author_facet | Brian Ritchey Qimin Hai Juying Han John Barnard Jonathan D Smith |
| author_sort | Brian Ritchey |
| collection | DOAJ |
| description | Quantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR Pycard genes only differ at a single-nucleotide polymorphism (SNP) in their 3’ untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of Pycard mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased Pycard mRNA stability without an increased transcription rate. CRISPR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the Pycard 3’UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced Pycard expression and inflammasome activity after cells were differentiated into macrophages due to reduced Pycard mRNA stability. |
| first_indexed | 2024-04-12T09:50:07Z |
| format | Article |
| id | doaj.art-c7679393149e4032b11ec2aec0bc0c57 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:50:07Z |
| publishDate | 2021-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c7679393149e4032b11ec2aec0bc0c572022-12-22T03:37:50ZengeLife Sciences Publications LtdeLife2050-084X2021-07-011010.7554/eLife.68203Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activityBrian Ritchey0Qimin Hai1Juying Han2John Barnard3Jonathan D Smith4https://orcid.org/0000-0002-0415-386XDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United StatesDepartment of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, United States; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, United StatesQuantitative trait locus mapping for interleukin-1β release after inflammasome priming and activation was performed on bone-marrow-derived macrophages (BMDM) from an AKRxDBA/2 mouse strain intercross. The strongest associated locus mapped very close to the Pycard gene on chromosome 7, which codes for the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). The DBA/2 and AKR Pycard genes only differ at a single-nucleotide polymorphism (SNP) in their 3’ untranslated region (UTR). DBA/2 vs. AKR BMDM had increased levels of Pycard mRNA expression and ASC protein, and increased inflammasome speck formation, which was associated with increased Pycard mRNA stability without an increased transcription rate. CRISPR/Cas9 gene editing was performed on DBA/2 embryonic stem cells to change the Pycard 3’UTR SNP from the DBA/2 to the AKR allele. This single base change significantly reduced Pycard expression and inflammasome activity after cells were differentiated into macrophages due to reduced Pycard mRNA stability.https://elifesciences.org/articles/68203inflammasomepost transcriptional regulationquantitative trait locus mappingstem cell derived macrophageshomology directed repair |
| spellingShingle | Brian Ritchey Qimin Hai Juying Han John Barnard Jonathan D Smith Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity eLife inflammasome post transcriptional regulation quantitative trait locus mapping stem cell derived macrophages homology directed repair |
| title | Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity |
| title_full | Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity |
| title_fullStr | Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity |
| title_full_unstemmed | Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity |
| title_short | Genetic variant in 3’ untranslated region of the mouse pycard gene regulates inflammasome activity |
| title_sort | genetic variant in 3 untranslated region of the mouse pycard gene regulates inflammasome activity |
| topic | inflammasome post transcriptional regulation quantitative trait locus mapping stem cell derived macrophages homology directed repair |
| url | https://elifesciences.org/articles/68203 |
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