A multimorphic variant in ThPOK causes a novel human disease characterized by T cell abnormalities, immunodysregulation, allergy, and fibrosis
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB75580 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR14689018.fastq.gz | Fastqsanger.gz | |||
| ERR14689019.fastq.gz | Fastqsanger.gz | |||
| ERR14689020.fastq.gz | Fastqsanger.gz | |||
| ERR14689021.fastq.gz | Fastqsanger.gz | |||
| ERR14689022.fastq.gz | Fastqsanger.gz |
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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.
2025-04-18 | GSE292581 | GEO
Project description:ChIP-seq data for ThPOK (ZBTB7B) target specificity for wild type and K360N mutant
| PRJEB87201 | ENA
Project description:ThPOK is a transcription factor which acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2: c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation, and ThPOKK360N-transduced fibroblasts with increased pro-fibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.
2025-03-23 | GSE291519 | GEO
Project description:ThPOK is a transcription factor which acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2: c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation, and ThPOKK360N-transduced fibroblasts with increased pro-fibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.
2025-03-23 | GSE291517 | GEO
Project description:ThPOK is a transcription factor which acts as a master regulator of CD4+ T cell lineage commitment. We report the first human disease caused by genetic alteration in ThPOK, specifically, a damaging heterozygous de novo variant in ThPOK (NM_001256455.2: c.1080A>C, p.K360N). This patient exhibited the unusual constellation of persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The ThPOKK360N variant displayed abnormal multimorphic activity, interfering with ThPOKWT (antimorph), failing to bind wild-type ThPOK consensus sequences (amorph), and showing novel DNA-binding specificity (neomorph). Single-cell RNA sequencing revealed defects in CD4+ and CD8+ T cell maturation and activation (hypomorph). Recapitulated in lentivirally transduced healthy control T cells and fibroblasts, transcriptomic analysis showed ThPOKK360N-transduced T cells had impaired TCR activation, and ThPOKK360N-transduced fibroblasts with increased pro-fibrotic gene expression. This novel human disease confirms ThPOK's role in CD4+ T cell development but also uncovers novel roles in TCR activation and regulation of fibrotic pathways in fibroblasts.
2025-03-23 | GSE291518 | GEO
Project description:The transcription factor ThPOK (encoded by Zbtb7b) is well known for its role as a master regulator of CD4 lineage commitment in the thymus. Here, we report a novel role for ThPOK as a critical and multifaceted regulator of myeloid lineage commitment, differentiation and maturation. Using reporter and knockout mouse models combined with CITE-Seq, Smart-Seq2, progenitor transfer and clonogenic assays and we show that ThPOK controls monocyte-DC versus granulocyte lineage production during homeostatic differentiation, and serves as a brake for neutrophil maturation in granulocyte lineage-specified cells through transcriptional regulation of lineage-specific transcription factors and RNA via altered mRNA splicing to reprogram intron retention.
2023-06-05 | GSE163843 | GEO
Project description:The transcription factor ThPOK (encoded by Zbtb7b) is well known for its role as a master regulator of CD4 lineage commitment in the thymus. Here, we report a novel role for ThPOK as a critical and multifaceted regulator of myeloid lineage commitment, differentiation and maturation. Using reporter and knockout mouse models combined with CITE-Seq, Smart-Seq2, progenitor transfer and clonogenic assays and we show that ThPOK controls monocyte-DC versus granulocyte lineage production during homeostatic differentiation, and serves as a brake for neutrophil maturation in granulocyte lineage-specified cells through transcriptional regulation of lineage-specific transcription factors and RNA via altered mRNA splicing to reprogram intron retention.
2023-06-05 | GSE163837 | GEO
Project description:The transcription factor Thpok is essential for CD4 T cell development in the thymus and remains expressed in post-thymic CD4 T cells. We post-thymically inactivated Thpok and compared microarray gene expression in Thpok-deficient CD4 T cells to that in their wildtype CD4 or CD8 counterparts We show that Thpok constrains the transcriptional circuitry to maintain CD4+-lineage integrity in naM-CM-/ve cells and to couple effector differentiation to environmental cues after antigenic stimulation. Redundantly with the related factor LRF, Thpok is continuously needed to prevent the trans-differentiation of mature CD4+ into -CD8+ T cells. We activated naM-CM-/ve CD4 T cells (either wild-type or Thpok-deficient) and CD8 T cells (wild-type) in vitro under Th1 conditions. Differentiated effectors were sorted 4 days after activation into CD4+CD8- and CD4-CD8+ (wild-type) and CD4+CD8- and CD4+CD8+ (Thpok-deficient) subsets. Total RNA was extracted from sorted subsets and processed for microarray analyses (Affymetrix Mouse Exon 1.0 ST array) at the NCI microarray facility, following the manufacturerM-bM-^@M-^Ys recommendation. Data is from 3 replicates (except wild-type CD4-CD8+ cells, for which two samples only were processed), generated from two distinct cell preparations.
2014-08-15 | E-GEOD-57846 | biostudies-arrayexpress
Project description:Although BTB-zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and expression of most CD4+- and CD8+-lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a novel Thpok cofactor. We locate three amino-acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions, and show that NuRD recruitment recapitulates the functions of the Thpok BTB domain. NuRD mediates Thpok repression of CD8+-lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-zinc finger factors, which control the differentiation of most hematopoietic subsets.
2022-06-10 | GSE199739 | GEO
Project description:To investigate the differences in DNA binding specificity of wild-type SALL4 C2H2 zinc finger cluster 4 (ZFC4) and disease causing mutations in SALL4 ZFC4, we performed SELEX coupled with high-throughput sequencing (HT-SELEX) using the purified wild-type SALL4 ZFC4 domain, mutated SALL4 ZFC4 (R900W) and mutated SALL4 ZFC4 (G921D) combined with no protein control experiment.
2023-01-04 | E-MTAB-11519 | biostudies-arrayexpress