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1.
Immunity ; 36(6): 921-32, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-22608498

ABSTRACT

Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1(-/-) NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.


Subject(s)
Killer Cells, Natural/immunology , Proto-Oncogene Protein c-ets-1/deficiency , Amino Acid Motifs , Animals , Binding Sites , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Inhibitor of Differentiation Protein 2/biosynthesis , Inhibitor of Differentiation Protein 2/genetics , Interleukin-15/pharmacology , Interleukin-15/physiology , Intracellular Signaling Peptides and Proteins/genetics , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Protein c-ets-1/physiology , Radiation Chimera , Receptors, Natural Killer Cell/biosynthesis , Receptors, Natural Killer Cell/genetics , Signal Transduction/genetics , Signal Transduction/immunology , T-Box Domain Proteins/biosynthesis , T-Box Domain Proteins/genetics , Transcription Factors/biosynthesis , Transcription Factors/genetics , Transcription, Genetic/drug effects , Transcription, Genetic/immunology
2.
PLoS Genet ; 6(9): e1001125, 2010 Sep 16.
Article in English | MEDLINE | ID: mdl-20862312

ABSTRACT

Aging is a complex phenotype responsive to a plethora of environmental inputs; yet only a limited number of transcriptional regulators are known to influence life span. How the downstream expression programs mediated by these factors (or others) are coordinated into common or distinct set of aging effectors is an addressable question in model organisms, such as C. elegans. Here, we establish the transcription factor ETS-4, an ortholog of vertebrate SPDEF, as a longevity determinant. Adult worms with ets-4 mutations had a significant extension of mean life span. Restoring ETS-4 activity in the intestine, but not neurons, of ets-4 mutant worms rescued life span to wild-type levels. Using RNAi, we demonstrated that ets-4 is required post-developmentally to regulate adult life span; thus uncoupling the role of ETS-4 in aging from potential functions in worm intestinal development. Seventy ETS-4-regulated genes, identified by gene expression profiling of two distinct ets-4 alleles and analyzed by bioinformatics, were enriched for known longevity effectors that function in lipid transport, lipid metabolism, and innate immunity. Putative target genes were enriched for ones that change expression during normal aging, the majority of which are controlled by the GATA factors. Also, some ETS-4-regulated genes function downstream of the FOXO factor, DAF-16 and the insulin/IGF-1 signaling pathway. However, epistasis and phenotypic analyses indicate that ets-4 functioned in parallel to the insulin/IGF-1 receptor, daf-2 and akt-1/2 kinases. Furthermore, ets-4 required daf-16 to modulate aging, suggesting overlap in function at the level of common targets that affect life span. In conclusion, ETS-4 is a new transcriptional regulator of aging, which shares transcriptional targets with GATA and FOXO factors, suggesting that overlapping pathways direct common sets of lifespan-related genes.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans/genetics , Caenorhabditis elegans/physiology , Longevity/genetics , Transcription Factors/metabolism , Transcription, Genetic , Animals , Base Sequence , Caenorhabditis elegans Proteins/metabolism , DNA, Helminth/metabolism , Forkhead Transcription Factors , Gene Deletion , Gene Expression Regulation, Developmental , Genes, Helminth/genetics , Insulin/metabolism , Insulin-Like Growth Factor I/metabolism , Intestinal Mucosa/metabolism , Larva/growth & development , Larva/metabolism , Models, Genetic , Mutation/genetics , Organ Specificity/genetics , Oviposition/genetics , Protein Binding , Signal Transduction/genetics , Transcription Factors/genetics
3.
Nat Struct Mol Biol ; 17(5): 620-8, 2010 May.
Article in English | MEDLINE | ID: mdl-20418882

ABSTRACT

RNA polymerase (Pol) III transcribes many noncoding RNAs (for example, transfer RNAs) important for translational capacity and other functions. We localized Pol III, alternative TFIIIB complexes (BRF1 or BRF2) and TFIIIC in HeLa cells to determine the Pol III transcriptome, define gene classes and reveal 'TFIIIC-only' sites. Pol III localization in other transformed and primary cell lines reveals previously uncharacterized and cell type-specific Pol III loci as well as one microRNA. Notably, only a fraction of the in silico-predicted Pol III loci are occupied. Many occupied Pol III genes reside within an annotated Pol II promoter. Outside of Pol II promoters, occupied Pol III genes overlap with enhancer-like chromatin and enhancer-binding proteins such as ETS1 and STAT1. Moreover, Pol III occupancy scales with the levels of nearby Pol II, active chromatin and CpG content. These results suggest that active chromatin gates Pol III accessibility to the genome.


Subject(s)
DNA Polymerase II/genetics , Gene Expression Profiling , RNA Polymerase III/genetics , Cell Line , Chromatin/metabolism , Enhancer Elements, Genetic , Genes , Genetic Loci , Genomics , HeLa Cells , Humans , Jurkat Cells , Promoter Regions, Genetic , Proto-Oncogene Protein c-ets-1/metabolism , RNA Polymerase III/analysis , RNA, Transfer/genetics , STAT1 Transcription Factor/metabolism
4.
PLoS Genet ; 5(12): e1000778, 2009 Dec.
Article in English | MEDLINE | ID: mdl-20019798

ABSTRACT

To elucidate how genomic sequences build transcriptional control networks, we need to understand the connection between DNA sequence and transcription factor binding and function. Binding predictions based solely on consensus predictions are limited, because a single factor can use degenerate sequence motifs and because related transcription factors often prefer identical sequences. The ETS family transcription factor, ETS1, exemplifies these challenges. Unexpected, redundant occupancy of ETS1 and other ETS proteins is observed at promoters of housekeeping genes in T cells due to common sequence preferences and the presence of strong consensus motifs. However, ETS1 exhibits a specific function in T cell activation; thus, unique transcriptional targets are predicted. To uncover the sequence motifs that mediate specific functions of ETS1, a genome-wide approach, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), identified both promoter and enhancer binding events in Jurkat T cells. A comparison with DNase I sensitivity both validated the dataset and also improved accuracy. Redundant occupancy of ETS1 with the ETS protein GABPA occurred primarily in promoters of housekeeping genes, whereas ETS1 specific occupancy occurred in the enhancers of T cell-specific genes. Two routes to ETS1 specificity were identified: an intrinsic preference of ETS1 for a variant of the ETS family consensus sequence and the presence of a composite sequence that can support cooperative binding with a RUNX transcription factor. Genome-wide occupancy of RUNX factors corroborated the importance of this partnership. Furthermore, genome-wide occupancy of co-activator CBP indicated tight co-localization with ETS1 at specific enhancers, but not redundant promoters. The distinct sequences associated with redundant versus specific ETS1 occupancy were predictive of promoter or enhancer location and the ontology of nearby genes. These findings demonstrate that diversity of DNA binding motifs may enable variable transcription factor function at different genomic sites.


Subject(s)
Core Binding Factor alpha Subunits/physiology , Gene Regulatory Networks , Proto-Oncogene Protein c-ets-1/physiology , Transcription Factors/physiology , Base Sequence , Binding Sites/genetics , Core Binding Factor alpha Subunits/metabolism , Enhancer Elements, Genetic , GA-Binding Protein Transcription Factor , Genome, Human , Humans , Jurkat Cells , Lymphocyte Activation , Promoter Regions, Genetic , Protein Binding , Proto-Oncogene Protein c-ets-1/metabolism , T-Lymphocytes , Transcription Factors/metabolism
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