Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis
IntroductionIn sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.848759/full |
| _version_ | 1811240593267884032 |
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| author | Christian Ascoli Cody A. Schott Yue Huang Benjamin A. Turturice Wangfei Wang Naomi Ecanow Nadera J. Sweiss Nadera J. Sweiss David L. Perkins Patricia W. Finn |
| author_facet | Christian Ascoli Cody A. Schott Yue Huang Benjamin A. Turturice Wangfei Wang Naomi Ecanow Nadera J. Sweiss Nadera J. Sweiss David L. Perkins Patricia W. Finn |
| author_sort | Christian Ascoli |
| collection | DOAJ |
| description | IntroductionIn sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity.MethodsMessenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts.ResultsWe identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion.ConclusionsAltered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression. |
| first_indexed | 2024-04-12T13:22:57Z |
| format | Article |
| id | doaj.art-5b1cf0d57fea42a1aa3ffbe103ee6255 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T13:22:57Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5b1cf0d57fea42a1aa3ffbe103ee62552022-12-22T03:31:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.848759848759Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosisChristian Ascoli0Cody A. Schott1Yue Huang2Benjamin A. Turturice3Wangfei Wang4Naomi Ecanow5Nadera J. Sweiss6Nadera J. Sweiss7David L. Perkins8Patricia W. Finn9Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesUniversity of Illinois at Chicago College of Medicine, Chicago, IL, United StatesDivision of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesUniversity of Illinois at Chicago College of Medicine, Chicago, IL, United StatesDepartment of Bioengineering, University of Illinois at Chicago College of Engineering and Medicine, Chicago, IL, United StatesUniversity of Illinois at Chicago College of Medicine, Chicago, IL, United StatesDivision of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDivision of Rheumatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDivision of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDivision of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesIntroductionIn sarcoidosis, peripheral lymphopenia and anergy have been associated with increased inflammation and maladaptive immune activity, likely promoting development of chronic and progressive disease. However, the molecular mechanisms that lead to reduced lymphocyte proportions, particularly CD4+ T-cells, have not been fully elucidated. We posit that paradoxical peripheral lymphopenia is characterized by a dysregulated transcriptomic network associated with cell function and fate that results from altered transcription factor targeting activity.MethodsMessenger RNA-sequencing (mRNA-seq) was performed on peripheral blood mononuclear cells (PBMCs) from ACCESS study subjects with sarcoidosis and matched controls and findings validated on a sarcoidosis case-control cohort and a sarcoidosis case series. Preserved PBMC transcriptomic networks between case-control cohorts were assessed to establish cellular associations with gene modules and define regulatory targeting involved in sarcoidosis immune dysregulation utilizing weighted gene co-expression network analysis and differential transcription factor involvement analysis. Network centrality measures identified master transcriptional regulators of subnetworks related to cell proliferation and death. Predictive models of differential PBMC proportions constructed from ACCESS target gene expression corroborated the relationship between aberrant transcription factor regulatory activity and imputed and clinical PBMC populations in the validation cohorts.ResultsWe identified two unique and preserved gene modules significantly associated with sarcoidosis immune dysregulation. Strikingly, increased expression of a monocyte-driven, and not a lymphocyte-driven, gene module related to innate immunity and cell death was the best predictor of peripheral CD4+ T-cell proportions. Within the gene network of this monocyte-driven module, TLE3 and CBX8 were determined to be master regulators of the cell death subnetwork. A core gene signature of differentially over-expressed target genes of TLE3 and CBX8 involved in cellular communication and immune response regulation accurately predicted imputed and clinical monocyte expansion and CD4+ T-cell depletion.ConclusionsAltered transcriptional regulation associated with aberrant gene expression of a monocyte-driven transcriptional network likely influences lymphocyte function and survival. Although further investigation is warranted, this indicates that crosstalk between hyperactive monocytes and lymphocytes may instigate peripheral lymphopenia and underlie sarcoidosis immune dysregulation and pathogenesis. Future therapies selectively targeting master regulators, or their targets, may mitigate dysregulated immune processes in sarcoidosis and disease progression.https://www.frontiersin.org/articles/10.3389/fimmu.2022.848759/fullsarcoidosistranscriptomicsimmune dysregulationmaster regulatorsPBMC |
| spellingShingle | Christian Ascoli Cody A. Schott Yue Huang Benjamin A. Turturice Wangfei Wang Naomi Ecanow Nadera J. Sweiss Nadera J. Sweiss David L. Perkins Patricia W. Finn Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis Frontiers in Immunology sarcoidosis transcriptomics immune dysregulation master regulators PBMC |
| title | Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| title_full | Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| title_fullStr | Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| title_full_unstemmed | Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| title_short | Altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| title_sort | altered transcription factor targeting is associated with differential peripheral blood mononuclear cell proportions in sarcoidosis |
| topic | sarcoidosis transcriptomics immune dysregulation master regulators PBMC |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.848759/full |
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