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BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells.

ABSTRACT: During T helper cell differentiation, distinct programs of gene expression play a key role in defining the immune response to an environmental challenge. How chromatin remodeling events at the associated cytokine loci control differentiation is not known. We found that the ATP-dependent remodeling enzyme subunit BRG1 was required for T helper 2 (Th2) differentiation and Th2 cytokine transcription. BRG1 binding to cytokine genes was regulated by the extent of differentiation, the extent of activation, and cell fate. BRG1 was required for some features of the chromatin structure in target genes (DNase I hypersensitivity and histone acetylation), suggesting that BRG1 remodeling activity was directly responsible for changes in gene expression. NFAT and STAT6 activity were required for BRG1 recruitment to the Th2 locus control region, and STAT6 associated with BRG1 in a differentiation-inducible manner, suggesting direct recruitment of BRG1 to the bound loci. Together, these findings suggest BRG1 interprets differentiation signals and plays a causal role in gene regulation, chromatin structure, and cell fate.

SUBMITTER: Wurster AL

PROVIDER: S-EPMC2593447 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells.

Wurster Andrea L AL Pazin Michael J MJ

Molecular and cellular biology 20081013 24

During T helper cell differentiation, distinct programs of gene expression play a key role in defining the immune response to an environmental challenge. How chromatin remodeling events at the associated cytokine loci control differentiation is not known. We found that the ATP-dependent remodeling enzyme subunit BRG1 was required for T helper 2 (Th2) differentiation and Th2 cytokine transcription. BRG1 binding to cytokine genes was regulated by the extent of differentiation, the extent of activa ...[more]

PMID: 18852284

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Project description:Nitrate is the main source of nitrogen for plants and an essential component of fertilizers. Rapid transcriptional activation of genes encoding the high-affinity nitrate transport system (HATS) is an important strategy that plants use to cope with nitrogen deficiency. However, the specific transcriptional machineries involved in this process and the detailed transcriptional regulatory mechanism of the core HATS remain poorly understood. ZmCHB101 is the core subunit of the SWI/SNF-type ATP-dependent chromatin remodeling complex in maize. RNA-interference transgenic plants (ZmCHB101-RNAi) display abaxially curling leaves and impaired tassel and cob development. Here, we demonstrate that ZmCHB101 plays a pivotal regulatory role in nitrate-responsive gene expression. ZmCHB101-RNAi lines showed accelerated root growth and increased biomass under low nitrate conditions. An RNA sequencing analysis revealed that ZmCHB101 regulates the expression of genes involved in nitrate transport, including ZmNRT2.1 and ZmNRT2.2. The NIN-like protein (NLP) of maize, ZmNLP3.1, recognized the consensus nitrate-responsive cis-elements (NREs) in the promoter regions of ZmNRT2.1 and ZmNRT2.2, and activated the transcription of these genes in response to nitrate. Intriguingly, well-positioned nucleosomes were detected at NREs in the ZmNRT2.1 and ZmNRT2.2 gene promoters, and nucleosome densities were lower in ZmCHB101-RNAi lines than in wild-type plants, both in the absence and presence of nitrate. The ZmCHB101 protein bound to NREs and was involved in the maintenance of nucleosome occupancies at these sites, which may impact the binding of ZmNLP3.1 to NREs in the absence of nitrate. However, in the presence of nitrate, the binding affinity of ZmCHB101 for NREs decreased dramatically, leading to reduced nucleosome density at NREs and consequently increased ZmNLP3.1 binding. Our results provide novel insights into the role of chromatin remodeling proteins in the regulation of nitrate-responsive gene expression in plants.

Project description:Brahma-related gene 1 (Brg1, also known as Smarca4 and Snf2?) encodes an adenosine-5'-triphosphate (ATP)-dependent catalytical subunit of the (switch/sucrose nonfermentable) (SWI/SNF) chromatin remodeling complexes. SWI/SNF complexes are recruited to chromatin through multiple mechanisms, including specific DNA-binding factors (for example, heat shock transcription factor 4 (Hsf4) and paired box gene 6 (Pax6)), chromatin structural proteins (for example, high-mobility group A1 (HMGA1)) and/or acetylated core histones. Previous studies have shown that a single amino acid substitution (K798R) in the Brg1 ATPase domain acts via a dominant-negative (dn) mechanism. Genetic studies have demonstrated that Brg1 is an essential gene for early (that is, prior implantation) mouse embryonic development. Brg1 also controls neural stem cell maintenance, terminal differentiation of multiple cell lineages and organs including the T-cells, glial cells and limbs.To examine the roles of Brg1 in mouse lens development, a dnBrg1 transgenic construct was expressed using the lens-specific ?A-crystallin promoter in postmitotic lens fiber cells. Morphological studies revealed abnormal lens fiber cell differentiation in transgenic lenses resulting in cataract. Electron microscopic studies showed abnormal lens suture formation and incomplete karyolysis (that is, denucleation) of lens fiber cells. To identify genes regulated by Brg1, RNA expression profiling was performed in embryonic day 15.5 (E15.5) wild-type and dnBrg1 transgenic lenses. In addition, comparisons between differentially expressed genes in dnBrg1 transgenic, Pax6 heterozygous and Hsf4 homozygous lenses identified multiple genes coregulated by Brg1, Hsf4 and Pax6. DNase II?, a key enzyme required for lens fiber cell denucleation, was found to be downregulated in each of the Pax6, Brg1 and Hsf4 model systems. Lens-specific deletion of Brg1 using conditional gene targeting demonstrated that Brg1 was required for lens fiber cell differentiation, for expression of DNase II?, for lens fiber cell denucleation and indirectly for retinal development.These studies demonstrate a cell-autonomous role for Brg1 in lens fiber cell terminal differentiation and identified DNase II? as a potential direct target of SWI/SNF complexes. Brg1 is directly or indirectly involved in processes that degrade lens fiber cell chromatin. The presence of nuclei and other organelles generates scattered light incompatible with the optical requirements for the lens.

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BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells.

Publications

BRG1-mediated chromatin remodeling regulates differentiation and gene expression of T helper cells.

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