ZBTB7B (ThPOK) IS REQUIRED FOR PATHOGENESIS OF CEREBRAL MALARIA AND PROTECTION AGAINST PULMONARY TUBERCULOSIS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA595854 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10699879_1.fastq.gz | Fastqsanger.gz | |||
| SRR10699879_2.fastq.gz | Fastqsanger.gz | |||
| SRR10699880_1.fastq.gz | Fastqsanger.gz | |||
| SRR10699880_2.fastq.gz | Fastqsanger.gz |
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Project description:We used a genome-wide screen in N-ethyl-N-nitrosourea (ENU)-mutagenized mice to identify genes in which recessive loss-of-function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein in which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single-positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of proinflammatory leukocytes in P. berghei ANKA-infected mice, and reduced production of proinflammatory cytokines by primary T cells ex vivo and in vivo. Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobacterium bovis BCG) and virulent (Mycobacterium tuberculosis H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK and causes loss of base contact by R367 in the major groove of the DNA, which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play key roles in CD4+ CD8+ T cell development and in the expression of lineage-specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.
2019-12-17 | GSE142069 | GEO
Project description:We used a genome-wide screen in N-ethyl-N-nitrosourea (ENU)-mutagenized mice to identify genes in which recessive loss-of-function mutations protect against pathological neuroinflammation. We identified an R367Q mutation in the ZBTB7B (ThPOK) protein in which homozygosity causes protection against experimental cerebral malaria (ECM) caused by infection with Plasmodium berghei ANKA. Zbtb7bR367Q homozygous mice show a defect in the lymphoid compartment expressed as severe reduction in the number of single-positive CD4 T cells in the thymus and in the periphery, reduced brain infiltration of proinflammatory leukocytes in P. berghei ANKA-infected mice, and reduced production of proinflammatory cytokines by primary T cells ex vivo and in vivo Dampening of proinflammatory immune responses in Zbtb7bR367Q mice is concomitant to increased susceptibility to infection with avirulent (Mycobacterium bovis BCG) and virulent (Mycobacterium tuberculosis H37Rv) mycobacteria. The R367Q mutation maps to the first DNA-binding zinc finger domain of ThPOK and causes loss of base contact by R367 in the major groove of the DNA, which is predicted to impair DNA binding. Global immunoprecipitation of ThPOK-containing chromatin complexes coupled to DNA sequencing (ChIP-seq) identified transcriptional networks and candidate genes likely to play key roles in CD4+ CD8+ T cell development and in the expression of lineage-specific functions of these cells. This study highlights ThPOK as a global regulator of immune function in which alterations may affect normal responses to infectious and inflammatory stimuli.
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Project description:The role of the transcription factor ThPOK, encoded by ZBTB7B, has not been formally established in humans since individuals with ThPOK deficiency or dysfunction have not yet been identified. We report the first case of a human with a damaging variant in ThPOK causing a syndrome encompassing CD4 T cell deficiency, allergic disease, severe fibrotic interstitial lung disease, global developmental delay, and growth failure. Trio whole-genome sequencing revealed a de novo variant (NM_001256455.2:c.1080A>C, p.K360N) in ZBTB7B. Despite normal expression, ThPOKK360N exhibited dysfunctional multimorphic activity. It demonstrated dominant-negative effects by hindering the capacity of ThPOKWT to regulate target gene expression (antimorph). Protein-DNA interaction assays showed inability of ThPOKK360N to bind to WT consensus sequences (amorph) and revealed a novel DNA-binding specificity (neomorph). Single-cell sequencing confirmed the patient's CD4 T cell deficiency, revealing that most T cells were less mature compared to healthy controls. Furthermore, naive CD4 and CD8 T cells showed diminished activation after stimulation. The link between ThPOKK360N and the patient’s symptoms was confirmed through lentiviral transduction experiments in healthy T cells and pulmonary fibroblasts. While T cells expressing ThPOKWT upregulated genes involved in activation, proliferation, and interferon responses, those with ThPOKK360N did not. When overexpressed in fibroblasts, ThPOKK360N significantly increased expression of pro-fibrotic genes implicated in pulmonary fibrosis. This description of a novel human disease caused by a multimorphic variant in ThPOK confirms its role in CD4 T cell development in an intact human context, while also revealing an unanticipated role for ThPOK in T cell function and fibrosis.
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