Distinct Foxp3 enhancer elements coordinate development, maintenance, and function of regulatory T cells.
Ryoji Kawakami1, Yohko Kitagawa1, Kelvin Y Chen2
1Department of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Department of Experimental Pathology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
Immunity
|April 30, 2021
Summary
Regulatory T (Treg) cell development relies on the transcription factor Foxp3. Specific DNA regions, Foxp3 CNS0 and CNS3, are essential for initiating and stabilizing Foxp3 expression, crucial for immune self-tolerance.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The transcription factor Foxp3 is vital for regulatory T (Treg) cell development and function.
- Conserved non-coding sequences (CNSs) within the Foxp3 locus regulate its transcription, but their developmental roles in Treg cell specification are not fully understood.
Purpose of the Study:
- To investigate the developmental contribution of Foxp3 CNSs to Treg cell lineage specification.
- To elucidate the mechanisms by which Foxp3 CNSs control Foxp3 gene expression during thymocyte differentiation.
Main Methods:
- Analysis of Foxp3 CNS activation during thymocyte differentiation.
- Assessment of thymocyte differentiation and Treg cell generation in mice with targeted deletion of Foxp3 CNSs.
- Evaluation of Foxp3 expression stability and immunological self-tolerance in mutant mice.
Main Results:
- Foxp3 CNS0 and CNS3 were activated sequentially before Foxp3 promoter activation, involving genomic looping.
- Deletion of either CNS0 or CNS3 partially impaired Treg cell generation.
- Combined deletion of CNS0 and CNS3 completely abolished Treg cell generation and stability, leading to lethal autoimmunity.
Conclusions:
- Hierarchical and coordinated activation of Foxp3 CNS0 and CNS3 is critical for initiating and stabilizing Foxp3 expression.
- These CNSs play a crucial role in Treg cell development, maintenance, and immunological self-tolerance.
Related Concept Videos
02:23Master Transcription Regulators
7.3K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
7.3K
02:23Master Transcription Regulators
2.4K
2.4K
01:30General Transcription Factors
6.2K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
6.2K
01:24T Cell Types and Functions
1.7K
When T cells with CD4 markers are activated, they give rise to two types of effector cells: helper T cells and regulatory T cells. Meanwhile, T cells with CD8 markers differentiate into effector cytotoxic T cells. The differentiation of CD4 T cells into helper T cell subsets, such as Th1, Th2, and Th17 cells, is dependent on the antigen type, antigen-presenting cell, and regulatory cytokines.
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
1.7K
02:16Transcription Factors
80.2K
Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
80.2K
02:36RNA Polymerase II Accessory Proteins
10.1K
Proteins that regulate transcription can do so either via direct contact with RNA Polymerase or through indirect interactions facilitated by adaptors, mediators, histone-modifying proteins, and nucleosome remodelers. Direct interactions to activate transcription is seen in bacteria as well as in some eukaryotic genes. In these cases, upstream activation sequences are adjacent to the promoters, and the activator proteins interact directly with the transcriptional machinery. For example, in...
10.1K