Journal article
Nuclear Role of WASp in the Pathogenesis of Dysregulated TH1 Immunity in Human Wiskott-Aldrich Syndrome
Science translational medicine, Vol.2(37), pp.37ra44-37ra44
06/23/2010
DOI: 10.1126/scitranslmed.3000813
PMCID: PMC2943146
PMID: 20574068
Abstract
The clinical symptomatology in the X-linked Wiskott-Aldrich syndrome (WAS), a combined immunodeficiency and autoimmune disease resulting from WAS protein (WASp) deficiency, reflects the underlying coexistence of an impaired T helper 1 (T
H
1) immunity alongside intact T
H
2 immunity. This suggests a role for WASp in patterning T
H
subtype immunity, yet the molecular basis for the T
H
1-T
H
2 imbalance in human WAS is unknown. We have discovered a nuclear role for WASp in the transcriptional regulation of the T
H
1 regulator gene
TBX21
at the chromatin level. In primary T
H
1-differentiating cells, a fraction of WASp is found in the nucleus, where it is recruited to the proximal promoter locus of the
TBX21
gene, but not to the core promoter of
GATA3
(a T
H
2 regulator gene) or
RORc
(a T
H
17 regulator gene). Genome-wide mapping demonstrates association of WASp in vivo with the gene-regulatory network that orchestrates T
H
1 cell fate choice in the human T
H
cell genome. Functionally, nuclear WASp associates with H3K4 trimethyltransferase [RBBP5 (retinoblastoma-binding protein 5)] and H3K9/H3K36 tridemethylase [JMJD2A (Jumonji domain-containing protein 2A)] proteins, and their enzymatic activity in vitro and in vivo is required for achieving transcription-permissive chromatin dynamics at the
TBX21
proximal promoter in primary differentiating T
H
1 cells. During T
H
1 differentiation, the loss of WASp accompanies decreased enrichment of RBBP5 and, in a subset of WAS patients, also of filamentous actin at the
TBX21
proximal promoter locus. Accordingly, human WASp-deficient T
H
cells, from natural mutation or RNA interference
–
mediated depletion, demonstrate repressed
TBX21
promoter dynamics when driven under T
H
1-differentiating conditions. These chromatin derangements accompany deficient T-BET messenger RNA and protein expression and impaired T
H
1 function, defects that are ameliorated by reintroducing WASp. Our findings reveal a previously unappreciated role of WASp in the epigenetic control of T-BET transcription and provide a new mechanism for the pathogenesis of WAS by linking aberrant histone methylation at the
TBX21
promoter to dysregulated adaptive immunity.
Details
- Title: Subtitle
- Nuclear Role of WASp in the Pathogenesis of Dysregulated TH1 Immunity in Human Wiskott-Aldrich Syndrome
- Creators
- Matthew D Taylor - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USASanjoy Sadhukhan - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAPonnappa Kottangada - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAArchana Ramgopal - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAKoustav Sarkar - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USASheryl D’Silva - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USAAnnamalai Selvakumar - Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10021, USAFabio Candotti - Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USAYatin M Vyas - Division of Pediatric Hematology-Oncology, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.2(37), pp.37ra44-37ra44
- DOI
- 10.1126/scitranslmed.3000813
- PMID
- 20574068
- PMCID
- PMC2943146
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Language
- English
- Date published
- 06/23/2010
- Academic Unit
- Stead Family Department of Pediatrics
- Record Identifier
- 9984093604902771
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