RESUMEN
The IKAROS family of transcription factors comprises four zinc-finger proteins (IKAROS, HELIOS, AIOLOS, and EOS), which over the last decades have been established to be critical regulators of the development and function of lymphoid cells. These factors act as homo- or heterodimers and are involved both in gene activation and repression. Their function often involves cross-talk with other regulatory circuits, such as the JAK/STAT, NF-κB, and NOTCH pathways. They control lymphocyte differentiation at multiple stages and are notably critical for lymphoid commitment in multipotent hematopoietic progenitors and for T and B cell differentiation downstream of pre-TCR and pre-BCR signaling. They also control many aspects of effector functions in mature B and T cells. They are dysregulated or mutated in multiple pathologies affecting the lymphoid system, which range from leukemia to immunodeficiencies. In this chapter, we review the molecular and physiological function of these factors in lymphocytes and their implications in human pathologies.
Asunto(s)
Diferenciación Celular , Factor de Transcripción Ikaros , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Animales , Transducción de Señal , Linfocitos/metabolismo , Linfocitos/inmunologíaRESUMEN
Ikaros family proteins (Ikaros, Helios, Aiolos, Eos) are zinc finger transcription factors essential for the development and function of the adaptive immune system. They also control developmental events in neurons and other cell types, suggesting that they possess crucial functions across disparate cell types. These functions are likely shared among the organisms in which these factors exist, and it is thus important to obtain a view of their distribution and conservation across organisms. How this family evolved remains poorly understood. Here we mined protein, mRNA and DNA databases to identify proteins with DNA-binding domains homologous to that of Ikaros. We show that Ikaros-related proteins exist in organisms from all four deuterostome phyla (chordates, echinoderms, hemichordates, xenacoelomorpha), but not in more distant groups. While most non-vertebrates have a single family member, this family grew to six members in the acoel worm Hofstenia miamia, three in jawless and four in jawed vertebrates. Most residues involved in DNA contact from zinc fingers 2 to 4 were identical across the Ikaros family, suggesting conserved mechanisms for target sequence recognition. Further, we identified a novel KRKxxxPxK/R motif that inhibits DNA binding in vitro which was conserved across the deuterostome phyla. We also identified a EψψxxxψM(D/E)QAIxxAIxYLGA(D/E)xL motif conserved among human Ikaros, Aiolos, Helios and subsets of chordate proteins, and motifs that are specific to subsets of vertebrate family members. Some of these motifs are targets of mutations in human patients. Finally we show that the atypical family member Pegasus emerged only in vertebrates, which is consistent with its function in bone. Our data provide a novel evolutionary perspective for Ikaros family proteins and suggest that they have conserved regulatory functions across deuterostomes.
Asunto(s)
Factor de Transcripción Ikaros , Dedos de Zinc , Animales , Humanos , ADN , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , ARN Mensajero , Dedos de Zinc/genéticaRESUMEN
Mutations in the gene encoding the zinc-finger transcription factor Ikaros (IKZF1) are found in patients with immunodeficiency, leukemia, and autoimmunity. Although Ikaros has a well-established function in modulating gene expression programs important for hematopoietic development, its role in other cell types is less well defined. Here, we uncover functions for Ikaros in thymic epithelial lineage development in mice and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both autoimmune regulator-positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity, and its deletion results in a marked expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals that Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
Asunto(s)
Tolerancia Central , Timo , Humanos , Ratones , Animales , Diferenciación Celular , Factores de Transcripción , Regulación de la Expresión GénicaRESUMEN
The transcriptional regulators that drive regulatory T (Treg) cell development and function remain partially understood. Helios (Ikzf2) and Eos (Ikzf4) are closely-related members of the Ikaros family of transcription factors. They are highly expressed in CD4+ Treg cells and functionally important for Treg cell biology, as mice deficient for either Helios or Eos are susceptible to autoimmune diseases. However, it remains unknown if these factors exhibit specific or partially redundant functions in Treg cells. Here we show that mice with germline deletions of both Ikzf2 and Ikzf4 are not very different from animals with single Ikzf2 or Ikzf4 deletions. Double knockout Treg cells differentiate normally, and efficiently suppress effector T cell proliferation in vitro. Both Helios and Eos are required for optimal Foxp3 protein expression. Surprisingly, Helios and Eos regulate different, largely non-overlapping, sets of genes. Only Helios is required for proper Treg cell aging, as Helios deficiency results in reduced Treg cell frequencies in the spleen of older animals. These results indicate that Helios and Eos are required for distinct aspects of Treg cell function.
Asunto(s)
Factor de Transcripción Ikaros , Linfocitos T Reguladores , Animales , Ratones , Enfermedades Autoinmunes/genética , Susceptibilidad a Enfermedades/metabolismo , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/metabolismo , Factores de Transcripción/metabolismoAsunto(s)
Factor de Transcripción Ikaros/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteínas de Fusión bcr-abl/genética , Humanos , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genéticaRESUMEN
Our understanding of cell fate decisions in hematopoietic stem cells is incomplete. Here, we show that the transcription factor Helios is highly expressed in murine hematopoietic stem and progenitor cells (HSPCs), where it is required to suppress the separation of the platelet/megakaryocyte lineage from the HSPC pool. Helios acts mainly in quiescent cells, where it directly represses the megakaryocyte gene expression program in cells as early as the stem cell stage. Helios binding promotes chromatin compaction, notably at the regulatory regions of platelet-specific genes recognized by the Gata2 and Runx1 transcriptional activators, implicated in megakaryocyte priming. Helios null HSPCs are biased toward the megakaryocyte lineage at the expense of the lymphoid and partially resemble cells of aging animals. We propose that Helios acts as a guardian of HSPC pluripotency by continuously repressing the megakaryocyte fate, which in turn allows downstream lymphoid priming to take place. These results highlight the importance of negative and positive priming events in lineage commitment.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Células Madre Hematopoyéticas/fisiología , Megacariocitos/fisiología , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Proteínas de Unión al ADN/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/citología , Linfocitos/citología , Linfocitos/fisiología , Masculino , Megacariocitos/citología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T/citología , Linfocitos T/fisiología , Factores de Transcripción/genéticaRESUMEN
The production of proinflammatory cytokines, particularly granulocyte-macrophage colony-stimulating factor (GM-CSF), by pathogenic CD4+ T cells is central for mediating tissue injury in inflammatory and autoimmune diseases. However, the factors regulating the T cell pathogenic gene expression program remain unclear. Here, we investigated how the Ikaros transcription factor regulates the global gene expression and chromatin accessibility changes in murine T cells during Th17 polarization and after activation via the T cell receptor (TCR) and CD28. We found that, in both conditions, Ikaros represses the expression of genes from the pathogenic signature, particularly Csf2, which encodes GM-CSF. We show that, in TCR/CD28-activated T cells, Ikaros binds a critical enhancer downstream of Csf2 and is required to regulate chromatin accessibility at multiple regions across this locus. Genome-wide Ikaros binding is associated with more compact chromatin, notably at multiple sites containing NFκB or STAT5 target motifs, and STAT5 or NFκB inhibition prevents GM-CSF production in Ikaros-deficient cells. Importantly, Ikaros also limits GM-CSF production in TCR/CD28-activated human T cells. Our data therefore highlight a critical conserved transcriptional mechanism that antagonizes GM-CSF expression in T cells.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor de Transcripción Ikaros/metabolismo , Activación de Linfocitos , Diferenciación Celular , Células Cultivadas , Epigenoma , Regulación de la Expresión Génica , HumanosRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0242211.].
RESUMEN
The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on >60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.
Asunto(s)
ADN/metabolismo , Factor de Transcripción Ikaros/metabolismo , Células Precursoras de Linfocitos B/metabolismo , Factor de Transcripción STAT5/metabolismo , Animales , Secuencia de Bases , Línea Celular , Cromatina/metabolismo , ADN/química , Factor de Transcripción Ikaros/deficiencia , Factor de Transcripción Ikaros/genética , Interleucina-17/farmacología , Ratones , Ratones Noqueados , Fosforilación , Células Precursoras de Linfocitos B/citología , Unión Proteica , Factor de Transcripción STAT5/genética , Proteínas Supresoras de la Señalización de Citocinas/química , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Regulación hacia Arriba/efectos de los fármacosAsunto(s)
Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Enfermedad Aguda , Secuencia de Bases , Haploinsuficiencia , Humanos , Factor de Transcripción Ikaros/biosíntesis , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Eliminación de SecuenciaRESUMEN
Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFß function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFß activation, suggesting that Ikaros is an upstream negative regulator of the TGFß pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFß-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity.
Asunto(s)
Diferenciación Celular/genética , Células Dendríticas/fisiología , Factor de Transcripción Ikaros/metabolismo , Receptores Notch/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Trasplante de Médula Ósea , Línea Celular , Regulación hacia Abajo , Células Madre Hematopoyéticas/fisiología , Factor de Transcripción Ikaros/genética , Ratones , Ratones Transgénicos , Monocitos/fisiología , Mutación , Transducción de Señal/genética , Regulación hacia ArribaRESUMEN
The IKZF family of transcription factors are essential regulators of lymphopoiesis. Ikaros, Helios, Aiolos and Eos function as transcriptional repressors and activators during T and B cell differentiation and in mature cell function, depending on the stage of development and/or cell type. Their potential mechanisms of action are varied. Ikaros family proteins partner with multiple complexes, including NuRD, PRC2 and transcription elongation factors, to modulate gene expression and the chromatin state. In humans, mutations in the IKZF genes are associated with B cell deficiency, leukemias and autoimmunity. In this review, we focus on the function of Ikaros family proteins in early T and B lymphocyte development, and discuss the molecular and physiological activities of this family.
Asunto(s)
Diferenciación Celular/genética , Factor de Transcripción Ikaros/genética , Linfocitos/citología , Linfocitos/metabolismo , Familia de Multigenes , Animales , Linaje de la Célula , Regulación de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/metabolismo , Subgrupos Linfocitarios/citología , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos/inmunología , Linfopoyesis/genética , Ratones , Transducción de SeñalRESUMEN
OBJECTIVE: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage. METHODS: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied. Symptoms were evaluated by visual scoring, quantification of paw swelling, determination of cytokine levels by enzyme-linked immunosorbent assay, and histologic analysis. Imiquimod-dependent therapeutic effects were monitored by transcriptome analysis (using quantitative reverse transcriptase-polymerase chain reaction) and flow cytometric analysis of the periarticular tissue. RESULTS: PDC-deficient mice showed exacerbation of inflammatory and arthritis symptoms after arthritogenic serum transfer. In contrast, enhancing PDC recruitment and activation to arthritic joints by topical application of the Toll-like receptor 7 (TLR-7) agonist imiquimod significantly ameliorated arthritis in various mouse models. Imiquimod induced an IFN signature and led to reduced infiltration of inflammatory cells. CONCLUSION: The therapeutic effects of imiquimod on joint inflammation and bone destruction are dependent on TLR-7 sensing by PDCs and type I IFN signaling. Our findings indicate that local recruitment and activation of PDCs represents an attractive therapeutic opportunity for RA patients.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Aminoquinolinas/farmacología , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Células Dendríticas/efectos de los fármacos , Interferón Tipo I/efectos de los fármacos , Animales , Artritis Experimental/genética , Artritis Reumatoide/genética , Citocinas/efectos de los fármacos , Citocinas/inmunología , Células Dendríticas/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/genética , Imiquimod , Interferón Tipo I/inmunología , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Receptor Toll-Like 7/genética , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Here, we unravel the mechanism of action of the Ikaros family zinc finger protein Helios (He) during the development of striatal medium spiny neurons (MSNs). He regulates the second wave of striatal neurogenesis involved in the generation of striatopallidal neurons, which express dopamine 2 receptor and enkephalin. To exert this effect, He is expressed in neural progenitor cells (NPCs) keeping them in the G1/G0 phase of the cell cycle. Thus, a lack of He results in an increase of S-phase entry and S-phase length of NPCs, which in turn impairs striatal neurogenesis and produces an accumulation of the number of cycling NPCs in the germinal zone (GZ), which end up dying at postnatal stages. Therefore, He-/- mice show a reduction in the number of dorso-medial striatal MSNs in the adult that produces deficits in motor skills acquisition. In addition, overexpression of He in NPCs induces misexpression of DARPP-32 when transplanted in mouse striatum. These findings demonstrate that He is involved in the correct development of a subset of striatopallidal MSNs and reveal new cellular mechanisms for neuronal development.
Asunto(s)
Cuerpo Estriado/citología , Proteínas de Unión al ADN/metabolismo , Globo Pálido/citología , Neuronas/citología , Neuronas/metabolismo , Factores de Transcripción/metabolismo , Animales , Animales Recién Nacidos , Recuento de Células , Puntos de Control del Ciclo Celular , Muerte Celular , Proliferación Celular , Ciclina E/metabolismo , Fase G1 , Ratones Noqueados , Actividad Motora , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Neurogénesis , Fenotipo , Fase SRESUMEN
We published a new method (BMC Bioinformatics 2014, 15:14) for searching for differentially expressed genes from two biological conditions datasets. The presentation of theorem 1 in this paper was incomplete. We received an anonymous comment about our publication that motivates the present work. Here, we present a complementary result which is necessary from the theoretical point of view to demonstrate our theorem. We also show that this result has no negative impact on our conclusions obtained with synthetic and experimental microarrays datasets.
Asunto(s)
Algoritmos , Biología Computacional/métodos , Interpretación Estadística de Datos , Perfilación de la Expresión Génica/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Simulación por Computador , Bases de Datos Genéticas , HumanosRESUMEN
Group 3 innate lymphoid cells (ILC3s) expressing the transcription factor (TF) RORγt are important for the defense and homeostasis of host intestinal tissues. The zinc finger TF Ikaros, encoded by Ikzf1, is essential for the development of RORγt(+) fetal lymphoid tissue inducer (LTi) cells and lymphoid organogenesis, but its role in postnatal ILC3s is unknown. Here, we show that small-intestinal ILC3s had lower Ikaros expression than ILC precursors and other ILC subsets. Ikaros inhibited ILC3s in a cell-intrinsic manner through zinc-finger-dependent inhibition of transcriptional activity of the aryl hydrocarbon receptor, a key regulator of ILC3 maintenance and function. Ablation of Ikzf1 in RORγt(+) ILC3s resulted in increased expansion and cytokine production of intestinal ILC3s and protection against infection and colitis. Therefore, in contrast to being required for LTi development, Ikaros inhibits postnatal ILC3 development and function to regulate gut immune responses at steady state and in disease.
Asunto(s)
Colitis/inmunología , Factor de Transcripción Ikaros/metabolismo , Mucosa Intestinal/inmunología , Linfocitos/fisiología , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Colitis/inducido químicamente , Sulfato de Dextran , Homeostasis , Factor de Transcripción Ikaros/genética , Inmunidad Innata , Mucosa Intestinal/microbiología , Activación de Linfocitos , Linfocitos/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Receptores de Hidrocarburo de Aril/genética , Transducción de Señal , Activación TranscripcionalRESUMEN
The Ikaros transcription factor is a tumor suppressor that is also important for lymphocyte development. How post-translational modifications influence Ikaros function remains partially understood. We show that Ikaros undergoes sumoylation in developing T cells that correspond to mono-, bi- or poly-sumoylation by SUMO1 and/or SUMO2/3 on three lysine residues (K58, K240 and K425). Sumoylation occurs in the nucleus and requires DNA binding by Ikaros. Sumoylated Ikaros is less effective than unsumoylated forms at inhibiting the expansion of murine leukemic cells, and Ikaros sumoylation is abundant in human B-cell acute lymphoblastic leukemic cells, but not in healthy peripheral blood leukocytes. Our results suggest that sumoylation may be important in modulating the tumor suppressor function of Ikaros.
Asunto(s)
Proteínas de Unión al ADN/genética , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcripción Genética , Animales , Linfocitos B/patología , Línea Celular Tumoral , Proteínas de Unión al ADN/biosíntesis , Regulación Neoplásica de la Expresión Génica , Humanos , Factor de Transcripción Ikaros/biosíntesis , Linfocitos/patología , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Procesamiento Proteico-Postraduccional/genética , Proteína SUMO-1/genética , Sumoilación/genética , Proteínas Supresoras de TumorRESUMEN
B1 B cells secrete most of the circulating natural antibodies and are considered key effector cells of the innate immune response. However, B1 cell-associated antibodies often cross-react with self-antigens, which leads to autoimmunity, and B1 cells have been implicated in cancer. How B1 cell activity is regulated remains unclear. We show that the Ikaros transcription factor is a major negative regulator of B1 cell development and function. Using conditional knock-out mouse models to delete Ikaros at different locations, we show that Ikaros-deficient mice exhibit specific and significant increases in splenic and bone marrow B1 cell numbers, and that the B1 progenitor cell pool is increased â¼10-fold in the bone marrow. Ikaros-null B1 cells resemble WT B1 cells at the molecular and cellular levels, but show a down-regulation of signaling components important for inhibiting proliferation and immunoglobulin production. Ikaros-null B1 cells hyper-react to TLR4 stimulation and secrete high amounts of IgM autoantibodies. These results indicate that Ikaros is required to limit B1 cell homeostasis in the adult.
Asunto(s)
Autoanticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Factor de Transcripción Ikaros/inmunología , Inmunoglobulina M/inmunología , Células Precursoras de Linfocitos B/inmunología , Animales , Factor de Transcripción Ikaros/genética , Ratones , Ratones Noqueados , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunologíaRESUMEN
The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.
Asunto(s)
Factor de Transcripción Ikaros/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal/fisiología , Bazo/citología , Animales , Linfocitos B , Proliferación Celular/fisiología , Células Cultivadas , Regulación de la Expresión Génica/fisiología , Ratones , Ratones Endogámicos C57BLRESUMEN
T-cell development is accompanied by epigenetic changes that ensure the silencing of stem cell-related genes and the activation of lymphocyte-specific programmes. How transcription factors influence these changes remains unclear. We show that the Ikaros transcription factor forms a complex with Polycomb repressive complex 2 (PRC2) in CD4(-)CD8(-) thymocytes and allows its binding to more than 500 developmentally regulated loci, including those normally activated in haematopoietic stem cells and others induced by the Notch pathway. Loss of Ikaros in CD4(-)CD8(-) cells leads to reduced histone H3 lysine 27 trimethylation and ectopic gene expression. Furthermore, Ikaros binding triggers PRC2 recruitment and Ikaros interacts with PRC2 independently of the nucleosome remodelling and deacetylation complex. Our results identify Ikaros as a fundamental regulator of PRC2 function in developing T cells.