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1.
Elife ; 112022 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-35699420

RESUMEN

Inflammatory chemokines and their receptors are central to the development of inflammatory/immune pathologies. The apparent complexity of this system, coupled with lack of appropriate in vivo models, has limited our understanding of how chemokines orchestrate inflammatory responses and has hampered attempts at targeting this system in inflammatory disease. Novel approaches are therefore needed to provide crucial biological, and therapeutic, insights into the chemokine-chemokine receptor family. Here, we report the generation of transgenic multi-chemokine receptor reporter mice in which spectrally distinct fluorescent reporters mark expression of CCRs 1, 2, 3, and 5, key receptors for myeloid cell recruitment in inflammation. Analysis of these animals has allowed us to define, for the first time, individual and combinatorial receptor expression patterns on myeloid cells in resting and inflamed conditions. Our results demonstrate that chemokine receptor expression is highly specific, and more selective than previously anticipated.


Asunto(s)
Quimiocinas , Inflamación , Animales , Proteínas Portadoras , Quimiocinas/genética , Quimiocinas/metabolismo , Expresión Génica , Inflamación/patología , Ratones
2.
Cell Rep ; 25(4): 988-1001, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30355503

RESUMEN

Transdifferentiation of fibroblasts into induced neuronal cells (iNs) by the neuron-specific transcription factors Brn2, Myt1l, and Ascl1 is a paradigmatic example of inter-lineage conversion across epigenetically distant cells. Despite tremendous progress regarding the transcriptional hierarchy underlying transdifferentiation, the enablers of the concomitant epigenome resetting remain to be elucidated. Here, we investigated the role of KMT2A and KMT2B, two histone H3 lysine 4 methylases with cardinal roles in development, through individual and combined inactivation. We found that Kmt2b, whose human homolog's mutations cause dystonia, is selectively required for iN conversion through suppression of the alternative myocyte program and induction of neuronal maturation genes. The identification of KMT2B-vulnerable targets allowed us, in turn, to expose, in a cohort of 225 patients, 45 unique variants in 39 KMT2B targets, which represent promising candidates to dissect the molecular bases of dystonia.


Asunto(s)
Transdiferenciación Celular , Distonía/genética , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Neuronas/patología , Animales , Diferenciación Celular/genética , Transdiferenciación Celular/genética , Embrión de Mamíferos/citología , Epigénesis Genética , Fibroblastos/citología , Histonas/metabolismo , Humanos , Lisina/metabolismo , Metilación , Ratones Noqueados , Neuronas/metabolismo , Transcriptoma/genética
3.
Elife ; 72018 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-29916805

RESUMEN

Hematopoietic stem cells require MLL1, which is one of six Set1/Trithorax-type histone 3 lysine 4 (H3K4) methyltransferases in mammals and clinically the most important leukemia gene. Here, we add to emerging evidence that all six H3K4 methyltransferases play essential roles in the hematopoietic system by showing that conditional mutagenesis of Setd1b in adult mice provoked aberrant homeostasis of hematopoietic stem and progenitor cells (HSPCs). Using both ubiquitous and hematopoietic-specific deletion strategies, the loss of Setd1b resulted in peripheral thrombo- and lymphocytopenia, multilineage dysplasia, myeloid-biased extramedullary hematopoiesis in the spleen, and lethality. By transplantation experiments and expression profiling, we determined that Setd1b is autonomously required in the hematopoietic lineages where it regulates key lineage specification components, including Cebpa, Gata1, and Klf1. Altogether, these data imply that the Set1/Trithorax-type epigenetic machinery sustains different aspects of hematopoiesis and constitutes a second framework additional to the transcription factor hierarchy of hematopoietic homeostasis.


Asunto(s)
Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , Homeostasis/genética , Linfopenia/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Trombocitopenia/genética , Animales , Trasplante de Médula Ósea , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Linaje de la Célula/genética , Factor de Transcripción GATA1/genética , Factor de Transcripción GATA1/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genes Letales , Células Madre Hematopoyéticas/citología , N-Metiltransferasa de Histona-Lisina/deficiencia , Isoenzimas/deficiencia , Isoenzimas/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Linfopenia/metabolismo , Linfopenia/patología , Ratones , Ratones Noqueados , Proteína de la Leucemia Mieloide-Linfoide/deficiencia , Bazo/metabolismo , Bazo/patología , Trombocitopenia/metabolismo , Trombocitopenia/patología , Irradiación Corporal Total
4.
J Neurosci ; 33(8): 3452-64, 2013 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-23426673

RESUMEN

The consolidation of long-term memories requires differential gene expression. Recent research has suggested that dynamic changes in chromatin structure play a role in regulating the gene expression program linked to memory formation. The contribution of histone methylation, an important regulatory mechanism of chromatin plasticity that is mediated by the counteracting activity of histone-methyltransferases and histone-demethylases, is, however, not well understood. Here we show that mice lacking the histone-methyltransferase myeloid/lymphoid or mixed-lineage leukemia 2 (mll2/kmt2b) gene in adult forebrain excitatory neurons display impaired hippocampus-dependent memory function. Consistent with the role of KMT2B in gene-activation DNA microarray analysis revealed that 152 genes were downregulated in the hippocampal dentate gyrus region of mice lacking kmt2b. Downregulated plasticity genes showed a specific deficit in histone 3 lysine 4 di- and trimethylation, while histone 3 lysine 4 monomethylation was not affected. Our data demonstrates that KMT2B mediates hippocampal histone 3 lysine 4 di- and trimethylation and is a critical player for memory formation.


Asunto(s)
Proteínas de Unión al ADN/fisiología , Memoria a Largo Plazo/fisiología , Proteínas de Neoplasias/fisiología , Animales , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Hipocampo/enzimología , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/genética , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Plasticidad Neuronal/genética , Plasticidad Neuronal/fisiología
5.
Protein Expr Purif ; 73(2): 132-9, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20510367

RESUMEN

Bovine lactoferricin (LFC) and bovine lactoferrampin (LFA) are two active fragments located in the N(1)-domain of bovine lactoferrin. Recent studies suggested that LFC and LFA have broad-spectrum activity against Gram-positive and Gram-negative bacteria. To date, LFC and LFA have usually been produced from milk. We report here the high-level expression, purification and characterization of LFC and LFA using the Photorhabdus luminescens expression system. After the cipA and cipB genes were deleted by ET recombination, the expression host P. luminescens TZR(001) was constructed. A synthetic LFC-LFA gene containing LFC and LFA was fused with the cipB gene to form a cipB-LFC-LFA gene. To obtain the expression vector pBAD-cipB-LFC-LFA, the cipB-LFC-LFA gene was cloned on the L-arabinose-inducible expression vector pBAD24. pBAD-cipB-LFC-LFA was transformed into P. luminescens TZR(001). The cipB-LFC-LFA fusion protein was expressed under the induction of L-arabinose and its yield reached 12 mg L(-1) bacterial culture. Recombinant LFC-LFA was released from cipB by pepsin. The MIC of recombinant LFC-LFA toward E. coli 0149, 0141 and 020 was 6.25, 12.5 and 3.175 microg ml(-1), respectively.


Asunto(s)
Antibacterianos/farmacología , Lactoferrina/aislamiento & purificación , Lactoferrina/metabolismo , Lactoglobulinas/aislamiento & purificación , Lactoglobulinas/metabolismo , Fragmentos de Péptidos/aislamiento & purificación , Fragmentos de Péptidos/metabolismo , Photorhabdus/metabolismo , Animales , Antibacterianos/aislamiento & purificación , Antibacterianos/metabolismo , Arabinosa/genética , Arabinosa/metabolismo , Bovinos , Escherichia coli/genética , Escherichia coli/metabolismo , Vectores Genéticos , Lactoferrina/genética , Lactoglobulinas/genética , Pruebas de Sensibilidad Microbiana , Fragmentos de Péptidos/genética , Photorhabdus/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/metabolismo
6.
J Invest Dermatol ; 125(6): 1228-35, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16354193

RESUMEN

So far, little is known about the physiological role of fatty acid transport protein 4 (Fatp4, Slc27a4). Mice with a targeted disruption of the Fatp4 gene display features of a human neonatally lethal restrictive dermopathy with a hyperproliferative hyperkeratosis, a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis, demonstrating that Fatp4 is necessary for the formation of the epidermal barrier. Because Fatp4 is widely expressed, it is unclear whether intrinsic Fatp4 deficiency in the epidermis alone can cause changes in the epidermal structure or whether the abnormalities observed are secondary to the loss of Fatp4 in other organs. To evaluate the functional role of Fatp4 in the skin, we generated a mouse line with Fatp4 deficiency inducible in the epidermis. Mice with epidermal keratinocyte-specific Fatp4 deficiency developed a hyperproliferative hyperkeratosis with a disturbed epidermal barrier. These changes resemble the histological abnormalities in the epidermis of newborn mice with total Fatp4 deficiency. We conclude that Fatp4 in epidermal keratinocytes is essential for the maintenance of a normal epidermal structure.


Asunto(s)
Epidermis/patología , Epidermis/fisiología , Proteínas de Transporte de Ácidos Grasos/deficiencia , Proteínas de Transporte de Ácidos Grasos/genética , Animales , Epidermis/efectos de los fármacos , Proteínas de Transporte de Ácidos Grasos/metabolismo , Femenino , Genotipo , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/patología , Ratones , Ratones Noqueados , Tamoxifeno/farmacología
7.
J Cell Biol ; 161(6): 1105-15, 2003 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-12821645

RESUMEN

The fatty acid transport protein family is a group of evolutionarily conserved proteins that are involved in the cellular uptake and metabolism of long and very long chain fatty acids. However, little is known about their respective physiological roles. To analyze the functional significance of fatty acid transport protein 4 (Fatp4, Slc27a4), we generated mice with a targeted disruption of the Fatp4 gene. Fatp4-null mice displayed features of a neonatally lethal restrictive dermopathy. Their skin was characterized by hyperproliferative hyperkeratosis with a disturbed epidermal barrier, a flat dermal-epidermal junction, a reduced number of pilo-sebaceous structures, and a compact dermis. The rigid skin consistency resulted in an altered body shape with facial dysmorphia, generalized joint flexion contractures, and impaired movement including suckling and breathing deficiencies. Lipid analysis demonstrated a disturbed fatty acid composition of epidermal ceramides, in particular a decrease in the C26:0 and C26:0-OH fatty acid substitutes. These findings reveal a previously unknown, essential function of Fatp4 in the formation of the epidermal barrier.


Asunto(s)
Epidermis/anomalías , Epidermis/metabolismo , Ácidos Grasos/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de Transporte de Membrana , Anomalías Cutáneas/metabolismo , Enfermedades Cutáneas Genéticas/metabolismo , Animales , Peso Corporal/genética , Proteínas Portadoras/genética , Ceramidas/biosíntesis , Modelos Animales de Enfermedad , Epidermis/patología , Proteínas de Transporte de Ácidos Grasos , Femenino , Marcación de Gen , Genes Letales/genética , Cabeza/anomalías , Cabeza/patología , Articulaciones/anomalías , Articulaciones/patología , Metabolismo de los Lípidos , Pulmón/anomalías , Pulmón/patología , Pulmón/ultraestructura , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Microscopía Electrónica , Mutación/genética , Fenotipo , Anomalías Cutáneas/genética , Enfermedades Cutáneas Genéticas/genética
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