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1.
Mol Cell ; 49(1): 158-71, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23159735

RESUMO

How the glucocorticoid receptor (GR) activates some genes while potently repressing others remains an open question. There are three current models for suppression: transrepression via GR tethering to AP-1/NF-κB sites, direct GR association with inhibitory elements (nGREs), and GR recruitment of the corepressor GRIP1. To gain insights into GR suppression, we used genomic analyses and genome-wide profiling of GR, p65, and c-Jun in LPS-stimulated macrophages. We show that GR mediates both activation and repression at tethered sites, GREs, and GRIP1-bound elements, indicating that motif classification is insufficient to predict regulatory polarity of GR binding. Interestingly, sites of GR repression utilize GRIP1's corepressor function and display reduced histone acetylation. Together, these findings suggest that while GR occupancy confers hormone responsiveness, the receptor itself may not participate in the regulatory effects. Furthermore, transcriptional outcome is not established by sequence but is influenced by epigenetic regulators, context, and other unrecognized regulatory determinants.


Assuntos
Epigênese Genética , Genoma , Inflamação/genética , Receptores de Glucocorticoides/fisiologia , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Células Cultivadas , Mapeamento Cromossômico , Análise por Conglomerados , Sequência Consenso , Dexametasona/farmacologia , Glucocorticoides/farmacologia , Histonas/metabolismo , Inflamação/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Processamento de Proteína Pós-Traducional , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Fatores de Transcrição/genética , Transcriptoma
2.
Proc Natl Acad Sci U S A ; 115(51): 13069-13074, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30478046

RESUMO

MicroRNAs (miRNAs) have been extensively reported to be associated with hematological malignancies. The loss of miR-15a/16-1 at chromosome 13q14 is a hallmark of most of human chronic lymphocytic leukemia (CLL). Deletion of murine miR-15a/16-1 and miR-15b/16-2 has been demonstrated to promote B cell malignancies. Here, we evaluate the biological role of miR-15/16 clusters, crossbreeding miR-15a/16-1 and miR-15b/16-2 knockout mice. Unexpectedly, the complete deletion of both clusters promoted myeloproliferative disorders in the majority of the mice by the age of 5 months with a penetrance of 70%. These mice showed a significant enlargement of spleen and abnormal swelling of lymph nodes. Flow cytometry characterization demonstrated an expanded CD11b/Gr-1 double-positive myeloid population both in spleen and in bone marrow. The transplantation of splenocytes harvested from double-KO mice into wild-type recipient mice resulted in the development of myeloproliferative disorders, as observed in the donors. In vivo, miR-15/16 cluster deletion up-regulated the expression of Cyclin D1, Cyclin D2, and Bcl-2. Taken together, our findings identify a driver oncogenic role for miR-15/16 cluster deletion in different leukocytic cell lineages.


Assuntos
Leucemia Mieloide Aguda/etiologia , MicroRNAs/fisiologia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Ciclinas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Linfonodos/metabolismo , Linfonodos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/metabolismo , Baço/patologia
3.
Proc Natl Acad Sci U S A ; 114(23): E4641-E4647, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28533390

RESUMO

Epithelial growth factor-like 7 (EGFL7) is a protein that is secreted by endothelial cells and plays an important role in angiogenesis. Although EGFL7 is aberrantly overexpressed in solid tumors, its role in leukemia has not been evaluated. Here, we report that levels of both EGFL7 mRNA and EGFL7 protein are increased in blasts of patients with acute myeloid leukemia (AML) compared with normal bone marrow cells. High EGFL7 mRNA expression associates with lower complete remission rates, and shorter event-free and overall survival in older (age ≥60 y) and younger (age <60 y) patients with cytogenetically normal AML. We further show that AML blasts secrete EGFL7 protein and that higher levels of EGFL7 protein are found in the sera from AML patients than in sera from healthy controls. Treatment of patient AML blasts with recombinant EGFL7 in vitro leads to increases in leukemic blast cell growth and levels of phosphorylated AKT. EGFL7 blockade with an anti-EGFL7 antibody reduced the growth potential and viability of AML cells. Our findings demonstrate that increased EGFL7 expression and secretion is an autocrine mechanism supporting growth of leukemic blasts in patients with AML.


Assuntos
Fatores de Crescimento Endotelial/genética , Fatores de Crescimento Endotelial/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Proteínas Angiogênicas/antagonistas & inibidores , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/metabolismo , Animais , Anticorpos Bloqueadores/farmacologia , Proteínas de Ligação ao Cálcio , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Família de Proteínas EGF , Fatores de Crescimento Endotelial/antagonistas & inibidores , Feminino , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Prognóstico , Proteínas/metabolismo , Proteínas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacologia , Fatores de Risco , Regulação para Cima , Adulto Jovem
4.
Genes Dev ; 24(24): 2760-5, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21106671

RESUMO

In the macrophage, toll-like receptors (TLRs) are key sensors that trigger signaling cascades to activate inflammatory programs via the NF-κB gene network. However, the genomic network targeted by TLR/NF-κB activation and the molecular basis by which it is restrained to terminate activation and re-establish quiescence is poorly understood. Here, using chromatin immunoprecipitation sequencing (ChIP-seq), we define the NF-κB cistrome, which is comprised of 31,070 cis-acting binding sites responsive to lipopolysaccharide (LPS)-induced signaling. In addition, we demonstrate that the transcriptional repressor B-cell lymphoma 6 (Bcl-6) regulates nearly a third of the Tlr4-regulated transcriptome, and that 90% of the Bcl-6 cistrome is collapsed following Tlr4 activation. Bcl-6-deficient macrophages are acutely hypersensitive to LPS and, using comparative ChIP-seq analyses, we found that the Bcl-6 and NF-κB cistromes intersect, within nucleosomal distance, at nearly half of Bcl-6-binding sites in stimulated macrophages to promote opposing epigenetic modifications of the local chromatin. These results reveal a genomic strategy for controlling the innate immune response in which repressive and inductive cistromes establish a dynamic balance between macrophage quiescence and activation via epigenetically marked cis-regulatory elements.


Assuntos
Proteínas de Ligação a DNA/genética , Elementos Facilitadores Genéticos/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Macrófagos/imunologia , NF-kappa B/genética , Animais , Sítios de Ligação , Células Cultivadas , Epigênese Genética , Lipopolissacarídeos/farmacologia , Camundongos , Proteínas Proto-Oncogênicas c-bcl-6 , Receptor 4 Toll-Like/genética
7.
Blood Adv ; 8(4): 947-958, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38181781

RESUMO

ABSTRACT: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT). Using preclinical mouse models of disease, previous work in our laboratory has linked microRNA-155 (miR-155) to the development of acute GVHD. Transplantation of donor T cells from miR-155 host gene (MIR155HG) knockout mice prevented acute GVHD in multiple murine models of disease while maintaining critical graft-versus-leukemia (GVL) response, necessary for relapse prevention. In this study, we used clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 genome editing to delete miR-155 in primary T cells (MIR155HGΔexon3) from human donors, resulting in stable and sustained reduction in expression of miR-155. Using the xenogeneic model of acute GVHD, we show that NOD/SCID/IL2rγnull (NSG) mice receiving MIR155HGΔexon3 human T cells provide protection from lethal acute GVHD compared with mice that received human T cells with intact miR-155. MIR155HGΔexon3 human T cells persist in the recipients displaying decreased proliferation potential, reduced pathogenic T helper-1 cell population, and infiltration into GVHD target organs, such as the liver and skin. Importantly, MIR155HGΔexon3 human T cells retain GVL response significantly improving survival in an in vivo model of xeno-GVL. Altogether, we show that CRISPR/Cas9-mediated deletion of MIR155HG in primary human donor T cells is an innovative approach to generate allogeneic donor T cells that provide protection from lethal GVHD while maintaining robust antileukemic response.


Assuntos
Doença Enxerto-Hospedeiro , MicroRNAs , Humanos , Camundongos , Animais , Incidência , Sistemas CRISPR-Cas , Camundongos Endogâmicos NOD , Camundongos SCID , Doença Enxerto-Hospedeiro/prevenção & controle , Camundongos Knockout , MicroRNAs/genética
8.
Leukemia ; 2024 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-39358541

RESUMO

Leukemias arise from recurrent clonal mutations in hematopoietic stem/progenitor cells (HSPCs) that cause profound changes in the bone marrow microenvironment (BMM) favoring leukemic stem cell (LSC) growth over normal HSPCs. Understanding the cross talk between preleukemic mutated HSPCs and the BMM is critical to develop novel therapeutic strategies to prevent leukemogenesis. We hypothesize that preleukemic-LSCs (pLSCs) induce BMM changes critical for leukemogenesis. Using our AML-murine model, we performed single-cell RNA-sequencing of preleukemic BMM (pBMM) cells. We found normal HSC (nHSC)-regulating LepR+ mesenchymal stem cells, and endothelial cells were decreased, along with increases in CD55+ fibroblasts and pericytes. Preleukemic CD55+ fibroblasts had higher proliferation rates and decreased collagen expression, suggesting extracellular matrix remodeling during leukemogenesis. Importantly, co-culture assays found preleukemic CD55+ fibroblasts expanded pLSCs significantly over nHSCs. In conclusion, we have identified a distinct pBMM and a novel CD55+ fibroblast population that is expanded in pBMM that promote fitness of pLSCs over nHSCs.

9.
Exp Hematol ; 123: 28-33.e3, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37209901

RESUMO

Mantle cell lymphoma (MCL) is an aggressive, noncurative, mature B-cell lymphoma, with a median overall survival of 6-7 years. This underlines a need for effective therapeutic strategies to treat MCL better. Epidermal growth factor-like 7 (EGFL7) is a protein secreted by endothelial cells shown to play a critical role in angiogenesis. Our laboratory has previously demonstrated that EGFL7 supports the growth of leukemic blasts in patients with acute myeloid leukemia (AML); however, its role in MCL has not been investigated yet. In this study, we report that EGFL7 messenger RNA (mRNA) is increased in the cells of patients with MCL compared with cells from healthy controls, and patients with high EGFL7 are associated with lower overall survival rates. Furthermore, EGFL7 is increased in the plasma of patients with MCL compared with the plasma from healthy controls. We further show that EGFL7 binds to epidermal growth factor receptor (EGFR) and activates AKT signaling pathway in MCL cells and that blocking EGFL7 in MCL in patient and cell lines decreases cell growth and increases apoptosis in vitro. Finally, anti-EGFL7 treatment inhibits tumor size and prolongs survival in a mouse model of MCL. In conclusion, our study reveals a role for EGFL7 in MCL cell proliferation and highlights EGFL7 inhibition as a promising new treatment for patients with MCL.


Assuntos
Linfoma de Célula do Manto , Animais , Camundongos , Linhagem Celular Tumoral , Família de Proteínas EGF/metabolismo , Células Endoteliais/metabolismo , Linfoma de Célula do Manto/metabolismo , Transdução de Sinais , Humanos
10.
Blood Adv ; 6(7): 2403-2408, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-34654057

RESUMO

Acute graft-versus-host disease (aGVHD) is the second most common cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), underscoring the need for novel therapies. Based on previous work that endothelial cell dysfunction is present in aGVHD and that epidermal growth factor-like domain 7 (EGFL7) plays a significant role in decreasing inflammation by repressing endothelial cell activation and T-cell migration, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD. Here, we show that treatment with recombinant EGFL7 (rEGFL7) in 2 different murine models of aGVHD decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft-versus-leukemia effect. Furthermore, we showed that rEGFL7 treatment results in higher thymocytes, T, B, and dendritic cell counts in recipient mice after allo-HSCT. This study constitutes a proof of concept of the ability of rEGFL7 therapy to reduce GHVD severity and mortality after allo-HSCT.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Animais , Transplante de Medula Óssea/efeitos adversos , Células Endoteliais , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Camundongos , Transplante Homólogo
11.
Nat Commun ; 11(1): 3702, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32710081

RESUMO

Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.


Assuntos
Transtornos da Insuficiência da Medula Óssea/etiologia , Medula Óssea/metabolismo , Traumatismos da Medula Espinal/complicações , Animais , Benzilaminas , Medula Óssea/patologia , Células da Medula Óssea , Transtornos da Insuficiência da Medula Óssea/patologia , Proliferação de Células , Quimiocina CXCL12 , Ciclamos , Modelos Animais de Doenças , Feminino , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Compostos Heterocíclicos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais , Traumatismos da Medula Espinal/imunologia
12.
Clin Cancer Res ; 26(3): 669-678, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672772

RESUMO

PURPOSE: EGF-like domain 7 (EGFL7) is a secreted protein and recently has been shown to play an important role in acute myeloid leukemia (AML); however, the underlying mechanism by which EGFL7 promotes leukemogenesis is largely unknown. EXPERIMENTAL DESIGN: Using an antibody interaction array, we measured the ability of EGFL7 to bind directly approximately 400 proteins expressed by primary AML blasts. Primary patient samples were stimulated in vitro with recombinant EGFL7 (rEGFL7) or anti-EGFL7 blocking antibody to assess alterations in downstream signaling and the ability to effect blast differentiation and survival. We treated three independent AML models with anti-EGFL7 or IgG1 control to determine whether anti-EGFL7 could prolong survival in vivo. RESULTS: We found EGFL7 significantly binds several signaling proteins important for normal and malignant hematopoiesis including NOTCH. Stimulation of AML blasts with rEGFL7 reduced NOTCH intracellular domain and NOTCH target gene expression while treatment with an anti-EGFL7 blocking antibody resulted in reactivation of NOTCH signaling, increased differentiation, and apoptosis. Competitive ligand-binding assays showed rEGFL7 inhibits DELTA-like (DLL) 4-mediated NOTCH activation while anti-EGFL7 combined with DLL4 significantly increased NOTCH activation and induced apoptosis. Using three different AML mouse models, we demonstrated that in vivo treatment with anti-EGFL7 alone results in increased survival. CONCLUSIONS: Our data demonstrate that EGFL7 contributes to NOTCH silencing in AML by antagonizing canonical NOTCH ligand binding. Reactivation of NOTCH signaling in vivo using anti-EGFL7 results in prolonged survival of leukemic mice, supporting the use of EGFL7 as a novel therapeutic target in AML.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Proteínas de Ligação ao Cálcio/metabolismo , Família de Proteínas EGF/metabolismo , Leucemia Mieloide Aguda/patologia , Receptores Notch/antagonistas & inibidores , Animais , Apoptose , Proteínas de Ligação ao Cálcio/genética , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Família de Proteínas EGF/genética , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores Notch/metabolismo , Transdução de Sinais
15.
Leukemia ; 33(9): 2169-2182, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30858548

RESUMO

In acute myeloid leukemia (AML), novel therapies are needed to target not only the rapidly dividing AML blasts but also the distinct population of leukemia stem cells (LSCs), which have abnormal self-renewal capacity and increased chemotherapy resistance. Elucidation of the expression and function of deregulated genes in LSCs is critical to specifically target LSCs and may consequently lead to improving outcomes of AML patients. Here, we correlated long non-coding RNA (lncRNA) expression profiles obtained from two RNA-seq datasets of 375 younger (aged <60 years) 76 older (≥60 years) adults with cytogenetically normal AML with a 'core enriched' (CE) gene expression signature (GES) associated with LSCs. We identified a LSC-specific signature of 111 lncRNAs that correlated strongly with the CE-GES. Among the top upregulated LSC-associated lncRNAs, we identified the lncRNA DANCR. Further experiments confirmed that DANCR is upregulated in functionally validated LSC-enriched populations. DANCR knock-down in LSCs resulted in decreased stem-cell renewal and quiescence. Furthermore, we showed that targeting Dancr in vivo using a primary murine model of AML (expressing both Mll partial tandem duplication/Flt3 internal tandem duplication) prolonged the survival of mice after serial transplantation. Our data suggest that LSCs have a distinct lncRNA signature with functional relevance and therapeutic potential.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Doença Aguda , Animais , Autorrenovação Celular/genética , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
16.
Nat Commun ; 10(1): 5351, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767858

RESUMO

Long non-coding RNAs (lncRNAs) are important regulatory molecules that are implicated in cellular physiology and pathology. In this work, we dissect the functional role of the HOXB-AS3 lncRNA in patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML). We show that HOXB-AS3 regulates the proliferative capacity of NPM1mut AML blasts in vitro and in vivo. HOXB-AS3 is shown to interact with the ErbB3-binding protein 1 (EBP1) and guide EBP1 to the ribosomal DNA locus. Via this mechanism, HOXB-AS3 regulates ribosomal RNA transcription and de novo protein synthesis. We propose that in the context of NPM1 mutations, HOXB-AS3 overexpression acts as a compensatory mechanism, which allows adequate protein production in leukemic blasts.


Assuntos
Leucemia Mieloide/genética , Mutação , Proteínas Nucleares/genética , RNA Longo não Codificante/genética , RNA Ribossômico/genética , Transcrição Gênica , Doença Aguda , Animais , Linhagem Celular Tumoral , Proliferação de Células , Células HEK293 , Humanos , Células K562 , Leucemia Mieloide/patologia , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Nucleofosmina , Biossíntese de Proteínas/genética , Células THP-1 , Transplante Heterólogo
17.
Nat Commun ; 4: 2354, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23965929

RESUMO

Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1). Here, we show that MG53 is an ubiquitin E3 ligase that induces IRS-1 ubiquitination with the help of an E2-conjugating enzyme, UBE2H. Molecular manipulations that disrupt the E3-ligase function of MG53 abolish IRS-1 ubiquitination and enhance skeletal myogenesis. Skeletal muscles derived from the MG53-/- mice show an elevated IRS-1 level with enhanced insulin signalling, which protects the MG53-/- mice from developing insulin resistance when challenged with a high-fat/high-sucrose diet. Muscle samples derived from human diabetic patients and mice with insulin resistance show normal expression of MG53, indicating that altered MG53 expression does not serve as a causative factor for the development of metabolic disorders. Thus, therapeutic interventions that target the interaction between MG53 and IRS-1 may be a novel approach for the treatment of metabolic diseases that are associated with insulin resistance.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Substratos do Receptor de Insulina/metabolismo , Insulina/metabolismo , Desenvolvimento Muscular/genética , Músculo Esquelético/metabolismo , Animais , Proteínas de Transporte/genética , Diferenciação Celular , Linhagem Celular , Diabetes Mellitus/metabolismo , Dieta Hiperlipídica , Teste de Tolerância a Glucose , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Masculino , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno , Transdução de Sinais , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinação
18.
Cell Metab ; 15(4): 554-62, 2012 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-22465074

RESUMO

Chronic inflammation is a hallmark of atherosclerosis, but its transcriptional underpinnings are poorly understood. We show that the transcriptional repressor Bcl6 is an anti-inflammatory regulator whose loss in bone marrow of Ldlr(-/-) mice results in severe atherosclerosis and xanthomatous tendonitis, a virtually pathognomonic complication in patients with familial hypercholesterolemia. Disruption of the interaction between Bcl6 and SMRT or NCoR with a peptide inhibitor in vitro recapitulated atherogenic gene changes in mice transplanted with Bcl6-deficient bone marrow, pointing to these cofactors as key mediators of Bcl6 inflammatory suppression. Using ChIP-seq, we reveal the SMRT and NCoR corepressor cistromes, each consisting of over 30,000 binding sites with a nearly 50% overlap. While the complete cistromes identify a diversity of signaling pathways, the Bcl6-bound subcistromes for each corepressor are highly enriched for NF-κB-driven inflammatory and tissue remodeling genes. These results reveal that Bcl6-SMRT/NCoR complexes constrain immune responses and contribute to the prevention of atherosclerosis.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Proteínas de Ligação a DNA/metabolismo , Inflamação/genética , Correpressor 2 de Receptor Nuclear/metabolismo , Animais , Aterosclerose/complicações , Sequência de Bases , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Colesterol/metabolismo , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/complicações , Inflamação/patologia , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Correpressor 2 de Receptor Nuclear/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Tendinopatia/patologia
19.
Cell Metab ; 13(3): 283-93, 2011 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-21356518

RESUMO

How type I skeletal muscle inherently maintains high oxidative and vascular capacity in the absence of exercise is unclear. We show that nuclear receptor ERRγ is highly expressed in type I muscle and, when transgenically expressed in anaerobic type II muscles (ERRGO mice), dually induces metabolic and vascular transformation in the absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration, and type I fiber specification. Muscles in ERRGO mice also display an activated angiogenic program marked by myofibrillar induction and secretion of proangiogenic factors, neovascularization, and a 100% increase in running endurance. Surprisingly, the induction of type I muscle properties by ERRγ does not involve PGC-1α. Instead, ERRγ genetically activates the energy sensor AMPK in mediating the metabovascular changes in ERRGO mice. Therefore, ERRγ represents a previously unrecognized determinant that specifies intrinsic vascular and oxidative metabolic features that distinguish type I from type II muscle.


Assuntos
Músculo Esquelético/metabolismo , Receptores de Estrogênio/metabolismo , Transativadores/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Animais , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Transgênicos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/fisiologia , Neovascularização Fisiológica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Proteínas Quinases/metabolismo , Fatores de Transcrição
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