C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9
The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, a...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75594 |
| _version_ | 1797998312008187904 |
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| author | Saskia-Larissa Jauch-Speer Marisol Herrera-Rivero Nadine Ludwig Bruna Caroline Véras De Carvalho Leonie Martens Jonas Wolf Achmet Imam Chasan Anika Witten Birgit Markus Bernhard Schieffer Thomas Vogl Jan Rossaint Monika Stoll Johannes Roth Olesja Fehler |
| author_facet | Saskia-Larissa Jauch-Speer Marisol Herrera-Rivero Nadine Ludwig Bruna Caroline Véras De Carvalho Leonie Martens Jonas Wolf Achmet Imam Chasan Anika Witten Birgit Markus Bernhard Schieffer Thomas Vogl Jan Rossaint Monika Stoll Johannes Roth Olesja Fehler |
| author_sort | Saskia-Larissa Jauch-Speer |
| collection | DOAJ |
| description | The proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout (KO)-based screening approach in immortalized murine monocytes, we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterized by S100a8 and S100a9 overexpression. |
| first_indexed | 2024-04-11T10:46:42Z |
| format | Article |
| id | doaj.art-54c2d245beda43d9b5ba5bca2657fa7e |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:46:42Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-54c2d245beda43d9b5ba5bca2657fa7e2022-12-22T04:29:03ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.75594C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9Saskia-Larissa Jauch-Speer0https://orcid.org/0000-0002-6739-3051Marisol Herrera-Rivero1https://orcid.org/0000-0001-7064-9487Nadine Ludwig2Bruna Caroline Véras De Carvalho3Leonie Martens4Jonas Wolf5Achmet Imam Chasan6https://orcid.org/0000-0001-5137-6890Anika Witten7Birgit Markus8Bernhard Schieffer9Thomas Vogl10Jan Rossaint11Monika Stoll12Johannes Roth13https://orcid.org/0000-0001-7035-8348Olesja Fehler14https://orcid.org/0000-0001-6386-7080Institute of Immunology, University of Münster, Münster, GermanyDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, GermanyDepartment of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, GermanyInstitute of Immunology, University of Münster, Münster, GermanyInstitute of Immunology, University of Münster, Münster, Germany; Department of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, GermanyInstitute of Immunology, University of Münster, Münster, GermanyInstitute of Immunology, University of Münster, Münster, GermanyDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany; Core Facility Genomics, Medical Faculty Münster, University of Münster, Münster, GermanyClinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, GermanyClinic for Cardiology, Angiology and Internal Intensive Medicine, University Hospital Marburg, Marburg, GermanyInstitute of Immunology, University of Münster, Münster, GermanyDepartment of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, GermanyDepartment of Genetic Epidemiology, Institute of Human Genetics, University of Münster, Münster, Germany; CARIM Cardiovascular Research School, Department of Biochemistry, Genetic Epidemiology and Statistical Genetics, Maastricht University, Maastricht, NetherlandsInstitute of Immunology, University of Münster, Münster, GermanyInstitute of Immunology, University of Münster, Münster, GermanyThe proinflammatory alarmins S100A8 and S100A9 are among the most abundant proteins in neutrophils and monocytes but are completely silenced after differentiation to macrophages. The molecular mechanisms of the extraordinarily dynamic transcriptional regulation of S100a8 and S100a9 genes, however, are only barely understood. Using an unbiased genome-wide CRISPR/Cas9 knockout (KO)-based screening approach in immortalized murine monocytes, we identified the transcription factor C/EBPδ as a central regulator of S100a8 and S100a9 expression. We showed that S100A8/A9 expression and thereby neutrophil recruitment and cytokine release were decreased in C/EBPδ KO mice in a mouse model of acute lung inflammation. S100a8 and S100a9 expression was further controlled by the C/EBPδ antagonists ATF3 and FBXW7. We confirmed the clinical relevance of this regulatory network in subpopulations of human monocytes in a clinical cohort of cardiovascular patients. Moreover, we identified specific C/EBPδ-binding sites within S100a8 and S100a9 promoter regions, and demonstrated that C/EBPδ-dependent JMJD3-mediated demethylation of H3K27me3 is indispensable for their expression. Overall, our work uncovered C/EBPδ as a novel regulator of S100a8 and S100a9 expression. Therefore, C/EBPδ represents a promising target for modulation of inflammatory conditions that are characterized by S100a8 and S100a9 overexpression.https://elifesciences.org/articles/75594C/EBPδcalprotectinCRISPR/Cas9 screenmonocytesS100A8/A9human |
| spellingShingle | Saskia-Larissa Jauch-Speer Marisol Herrera-Rivero Nadine Ludwig Bruna Caroline Véras De Carvalho Leonie Martens Jonas Wolf Achmet Imam Chasan Anika Witten Birgit Markus Bernhard Schieffer Thomas Vogl Jan Rossaint Monika Stoll Johannes Roth Olesja Fehler C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 eLife C/EBPδ calprotectin CRISPR/Cas9 screen monocytes S100A8/A9 human |
| title | C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 |
| title_full | C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 |
| title_fullStr | C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 |
| title_full_unstemmed | C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 |
| title_short | C/EBPδ-induced epigenetic changes control the dynamic gene transcription of S100a8 and S100a9 |
| title_sort | c ebpδ induced epigenetic changes control the dynamic gene transcription of s100a8 and s100a9 |
| topic | C/EBPδ calprotectin CRISPR/Cas9 screen monocytes S100A8/A9 human |
| url | https://elifesciences.org/articles/75594 |
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