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1.
Nat Immunol ; 21(3): 261-273, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32066955

RESUMEN

Crosstalk between mesenchymal stromal cells (MSCs) and hematopoietic stem cells (HSCs) is essential for hematopoietic homeostasis and lineage output. Here, we investigate how transcriptional changes in bone marrow (BM) MSCs result in long-lasting effects on HSCs. Single-cell analysis of Cxcl12-abundant reticular (CAR) cells and PDGFRα+Sca1+ (PαS) cells revealed an extensive cellular heterogeneity but uniform expression of the transcription factor gene Ebf1. Conditional deletion of Ebf1 in these MSCs altered their cellular composition, chromatin structure and gene expression profiles, including the reduced expression of adhesion-related genes. Functionally, the stromal-specific Ebf1 inactivation results in impaired adhesion of HSCs, leading to reduced quiescence and diminished myeloid output. Most notably, HSCs residing in the Ebf1-deficient niche underwent changes in their cellular composition and chromatin structure that persist in serial transplantations. Thus, genetic alterations in the BM niche lead to long-term functional changes of HSCs.


Asunto(s)
Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Transactivadores/deficiencia , Animales , Adhesión Celular/genética , Adhesión Celular/fisiología , Autorrenovación de las Células/genética , Autorrenovación de las Células/fisiología , Cromatina/genética , Femenino , Hematopoyesis/genética , Hematopoyesis/fisiología , Trasplante de Células Madre Hematopoyéticas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Análisis de la Célula Individual , Nicho de Células Madre/genética , Nicho de Células Madre/fisiología , Transactivadores/genética , Transcriptoma
2.
Immunity ; 54(11): 2465-2480.e5, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34706222

RESUMEN

Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.


Asunto(s)
Metilación de ADN , Epigénesis Genética , Epigenómica , Regulación de la Expresión Génica , Inmunidad , Factores de Transcripción/metabolismo , Transcriptoma , Epigenómica/métodos , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Factores de Transcripción/genética
3.
Genes Dev ; 35(15-16): 1142-1160, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-34244292

RESUMEN

The establishment of cell fates involves alterations of transcription factor repertoires and repurposing of transcription factors by post-translational modifications. In embryonic stem cells (ESCs), the chromatin organizers SATB2 and SATB1 balance pluripotency and differentiation by activating and repressing pluripotency genes, respectively. Here, we show that conditional Satb2 gene inactivation weakens ESC pluripotency, and we identify SUMO2 modification of SATB2 by the E3 ligase ZFP451 as a potential driver of ESC differentiation. Mutations of two SUMO-acceptor lysines of Satb2 (Satb2K →R ) or knockout of Zfp451 impair the ability of ESCs to silence pluripotency genes and activate differentiation-associated genes in response to retinoic acid (RA) treatment. Notably, the forced expression of a SUMO2-SATB2 fusion protein in either Satb2K →R or Zfp451-/- ESCs rescues, in part, their impaired differentiation potential and enhances the down-regulation of Nanog The differentiation defect of Satb2K →R ESCs correlates with altered higher-order chromatin interactions relative to Satb2wt ESCs. Upon RA treatment of Satb2wt ESCs, SATB2 interacts with ZFP451 and the LSD1/CoREST complex and gains binding at differentiation genes, which is not observed in RA-treated Satb2K →R cells. Thus, SATB2 SUMOylation may contribute to the rewiring of transcriptional networks and the chromatin interactome of ESCs in the transition of pluripotency to differentiation.


Asunto(s)
Células Madre Embrionarias , Sumoilación , Ubiquitina-Proteína Ligasas/metabolismo , Diferenciación Celular/genética , Cromatina/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
4.
Genes Dev ; 34(21-22): 1503-1519, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004416

RESUMEN

EBF1 and PAX5 mutations are associated with the development of B progenitor acute lymphoblastic leukemia (B-ALL) in humans. To understand the molecular networks driving leukemia in the Ebf1+/-Pax5+/- (dHet) mouse model for B-ALL, we interrogated the transcriptional profiles and chromatin status of leukemic cells, preleukemic dHet pro-B, and wild-type pro-B cells with the corresponding EBF1 and Pax5 cistromes. In dHet B-ALL cells, many EBF1 and Pax5 target genes encoding pre-BCR signaling components and transcription factors were down-regulated, whereas Myc and genes downstream from IL-7 signaling or associated with the folate pathway were up-regulated. We show that blockade of IL-7 signaling in vivo and methotrexate treatment of leukemic cells in vitro attenuate the expansion of leukemic cells. Single-cell RNA-sequencing revealed heterogeneity of leukemic cells and identified a subset of wild-type pro-B cells with reduced Ebf1 and enhanced Myc expression that show hallmarks of dHet B-ALL cells. Thus, EBF1 and Pax5 may safeguard early stage B cells from transformation to B-ALL by limiting IL-7 signaling, folate metabolism and Myc expression.


Asunto(s)
Ácido Fólico/metabolismo , Interleucina-7/fisiología , Factor de Transcripción PAX5/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , Proteínas Proto-Oncogénicas c-myc/genética , Transducción de Señal/genética , Transactivadores/metabolismo , Animales , Carbono/metabolismo , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Ratones , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfocitos B/patología , Unión Proteica , Análisis de la Célula Individual , Transactivadores/genética
6.
Genes Dev ; 32(2): 96-111, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29440261

RESUMEN

B-cell fate determination requires the action of transcription factors that operate in a regulatory network to activate B-lineage genes and repress lineage-inappropriate genes. However, the dynamics and hierarchy of events in B-cell programming remain obscure. To uncouple the dynamics of transcription factor expression from functional consequences, we generated induction systems in developmentally arrested Ebf1-/- pre-pro-B cells to allow precise experimental control of EBF1 expression in the genomic context of progenitor cells. Consistent with the described role of EBF1 as a pioneer transcription factor, we show in a time-resolved analysis that EBF1 occupancy coincides with EBF1 expression and precedes the formation of chromatin accessibility. We observed dynamic patterns of EBF1 target gene expression and sequential up-regulation of transcription factors that expand the regulatory network at the pro-B-cell stage. A continuous EBF1 function was found to be required for Cd79a promoter activity and for the maintenance of an accessible chromatin domain that is permissive for binding of other transcription factors. Notably, transient EBF1 occupancy was detected at lineage-inappropriate genes prior to their silencing in pro-B cells. Thus, persistent and transient functions of EBF1 allow for an ordered sequence of epigenetic and transcriptional events in B-cell programming.


Asunto(s)
Linfocitos B/metabolismo , Epigénesis Genética , Células Madre/metabolismo , Transactivadores/metabolismo , Transcripción Genética , Animales , Antígenos CD79/genética , Linaje de la Célula/genética , Células Cultivadas , Cromatina/metabolismo , ADN/metabolismo , Ratones , Factor de Transcripción PAX5/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo
7.
Nat Immunol ; 14(8): 867-75, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23812095

RESUMEN

The transcription factors EBF1 and Pax5 have been linked to activation of the B cell lineage program and irreversible loss of alternative lineage potential (commitment), respectively. Here we conditionally deleted Ebf1 in committed pro-B cells after transfer into alymphoid mice. We found that those cells converted into innate lymphoid cells (ILCs) and T cells with variable-diversity-joining (VDJ) rearrangements of loci encoding both B cell and T cell antigen receptors. As intermediates in lineage conversion, Ebf1-deficient CD19(+) cells expressing Pax5 and transcriptional regulators of the ILC and T cell fates were detectable. In particular, genes encoding the transcription factors Id2 and TCF-1 were bound and repressed by EBF1. Thus, both EBF1 and Pax5 are required for B lineage commitment by repressing distinct and common determinants of alternative cell fates.


Asunto(s)
Linfocitos B/inmunología , Transactivadores/inmunología , Traslado Adoptivo , Animales , Linfocitos B/citología , Diferenciación Celular/inmunología , Linaje de la Célula , ADN/química , ADN/genética , Regulación de la Expresión Génica , Linfopoyesis/inmunología , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Transactivadores/genética , Recombinación V(D)J/genética , Recombinación V(D)J/inmunología
8.
Immunity ; 44(3): 527-541, 2016 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-26982363

RESUMEN

Lymphopoiesis requires the activation of lineage-specific genes embedded in naive, inaccessible chromatin or in primed, accessible chromatin. The mechanisms responsible for de novo gain of chromatin accessibility, known as "pioneer" function, remain poorly defined. Here, we showed that the EBF1 C-terminal domain (CTD) is required for the regulation of a specific gene set involved in B cell fate decision and differentiation, independently of activation and repression functions. Using genome-wide analysis of DNaseI hypersensitivity and DNA methylation in multipotent Ebf1(-/-) progenitors and derivative EBF1wt- or EBF1ΔC-expressing cells, we found that the CTD promoted chromatin accessibility and DNA demethylation in previously naive chromatin. The CTD allowed EBF1 to bind at inaccessible genomic regions that offer limited co-occupancy by other transcription factors, whereas the CTD was dispensable for EBF1 binding at regions that are occupied by multiple transcription factors. Thus, the CTD enables EBF1 to confer permissive lineage-specific changes in progenitor chromatin landscape.


Asunto(s)
Linfocitos B/fisiología , Cromatina/metabolismo , Células Progenitoras Linfoides/fisiología , Transactivadores/metabolismo , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Metilación de ADN/genética , Redes Reguladoras de Genes/genética , Linfopoyesis , Ratones , Ratones Noqueados , Ratones Transgénicos , Estructura Terciaria de Proteína/genética , Transactivadores/genética
9.
Br J Haematol ; 204(2): 595-605, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-37945316

RESUMEN

Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1.


Asunto(s)
Leucemia Mielomonocítica Juvenil , Neurofibromatosis 1 , Niño , Humanos , Leucemia Mielomonocítica Juvenil/genética , Neurofibromatosis 1/genética , Mutación , Transducción de Señal , Genes Supresores de Tumor
10.
Haematologica ; 109(2): 422-430, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-37584291

RESUMEN

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (range, 0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to myelodysplastic syndrome with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (range, 14-40) from diagnosis for MDSEB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT (clinicaltrials gov. Identifier: NCT00662090).


Asunto(s)
Deleción Cromosómica , Síndromes Mielodisplásicos , Humanos , Niño , Preescolar , Lactante , Remisión Espontánea , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Progresión de la Enfermedad , Factores de Transcripción/genética , Monosomía , Cromosomas Humanos Par 7/genética , Péptidos y Proteínas de Señalización Intracelular/genética
11.
Genes Dev ; 30(20): 2310-2324, 2016 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-27807034

RESUMEN

Transcription factor EBF1 (early B-cell factor 1) regulates early B-cell differentiation by poising or activating lineage-specific genes and repressing genes associated with alternative cell fates. To identify proteins that regulate the diverse functions of EBF1, we used SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry of proteins associated with endogenous EBF1 in pro-B cells. This analysis identified most components of the multifunctional CCR4-NOT complex, which regulates transcription and mRNA degradation. CNOT3 interacts with EBF1, and we identified histidine 240 in EBF1 as a critical residue for this interaction. Complementation of Ebf1-/- progenitors with EBF1H240A revealed a partial block of pro-B-cell differentiation and altered expression of specific EBF1 target genes that show either reduced transcription or increased mRNA stability. Most deregulated EBF1 target genes show normal occupancy by EBF1H240A, but we also detected genes with altered occupancy, suggesting that the CCR4-NOT complex affects multiple activities of EBF1. Mice with conditional Cnot3 inactivation recapitulate the block of early B-cell differentiation, which we found to be associated with an impaired autoregulation of Ebf1 and reduced expression of pre-B-cell receptor components. Thus, the interaction of the CCR4-NOT complex with EBF1 diversifies the function of EBF1 in a context-dependent manner and may coordinate transcriptional and post-transcriptional gene regulation.


Asunto(s)
Linfocitos B/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Regulación de la Expresión Génica/genética , Proteínas de Homeodominio/metabolismo , Linfopoyesis/genética , Proteínas Nucleares/metabolismo , Estabilidad del ARN/genética , Factores de Transcripción/metabolismo , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/genética , Silenciador del Gen , Células HEK293 , Proteínas de Homeodominio/genética , Humanos , Ratones , Chaperonas Moleculares/genética , Mutación , Proteínas Nucleares/genética , Unión Proteica , Factores de Transcripción/genética , Transgenes
12.
BMC Genomics ; 23(1): 247, 2022 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-35361117

RESUMEN

BACKGROUND: Chromatin architecture is critical for gene expression during development. Matrix attachment regions (MARs) control and regulate chromatin dynamics. The position of MARs in the genome determines the expression of genes in the organism. In this study, we set out to elucidate how MARs temporally regulate the expression of the fibroin heavy chain (FIBH) gene during development. We addressed this by identifying MARs and studying their distribution and differentiation, in the posterior silk glands of Bombyx mori during 5th instar development. RESULTS: Of the MARs identified on three different days, 7.15% MARs were common to all 3 days, whereas, 1.41, 19.27 and 52.47% MARs were unique to day 1, day 5, and day 7, respectively highlighting the dynamic nature of the matrix associated DNA. The average chromatin loop length based on the chromosome wise distribution of MARs and the distances between these MAR regions decreased from day 1 (253.91 kb) to day 5 (73.54 kb) to day 7 (39.19 kb). Further significant changes in the MARs in the vicinity of the FIBH gene were found during different days of 5th instar development which implied their role in the regulation and expression of the FIBH gene. CONCLUSIONS: The presence of MARs in the flanking regions of genes found to exhibit differential expression during 5th instar development indicates their possible role in the regulation of their expression. This reiterates the importance of MARs in the genomic functioning as regulators of the molecular mechanisms in the nucleus. This is the first study that takes into account the tissue specific genome-wide MAR association and the potential role of these MARs in developmentally regulated gene expression. The current study lays a foundation to understand the genome wide regulation of chromatin during development.


Asunto(s)
Bombyx , Fibroínas , Animales , Bombyx/genética , Bombyx/metabolismo , Cromatina/metabolismo , Fibroínas/genética , Fibroínas/metabolismo , Regiones de Fijación a la Matriz , Seda/genética
13.
Proc Natl Acad Sci U S A ; 115(41): E9630-E9639, 2018 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-30257949

RESUMEN

Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1-/-Prdm1+/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1-/- plasmablasts show a reduced activation of ß1-integrin, which contributes to the impaired plasmablast differentiation and migration of antibody-secreting cells to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation.


Asunto(s)
Células de la Médula Ósea/metabolismo , Diferenciación Celular/fisiología , Integrina beta1/metabolismo , Chaperonas Moleculares/metabolismo , Células Plasmáticas/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Animales , Células de la Médula Ósea/citología , Inmunoglobulina M/genética , Inmunoglobulina M/metabolismo , Integrina beta1/genética , Ratones , Ratones Noqueados , Chaperonas Moleculares/genética , Células Plasmáticas/citología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética
14.
Exp Hematol ; 133: 104207, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38522505

RESUMEN

Myelodysplastic/myeloproliferative diseases of childhood cause a relevant disease burden, and many of these diseases may have a fatal course. The use of next-generation sequencing (NGS) has led to the identification of novel genetic variants in patients with these diseases, advancing our understanding of the underlying pathophysiology. However, novel mutations can often only be interpreted as variants of unknown significance (VUS), hindering adequate diagnosis and the use of a targeted therapy. To improve variant interpretation and test targeted therapies in a preclinical setting, we are using a rapid zebrafish embryo model that allows functional evaluation of the novel variant and possible therapeutic approaches within days. Thereby, we accelerate the translation from genetic findings to treatment options. Here, we establish this workflow on a novel in-frame tandem duplication in NRAS (c.192_227dup; p.G75_E76insDS65_G75) identified by Sanger sequencing in a 2.5-year-old patient with an unclassifiable myelodysplastic/myeloproliferative neoplasm (MDS/MPN-U). We show that this variant results in a myeloproliferative phenotype in zebrafish embryos with expansion of immature myeloid cells in the caudal hematopoietic tissue, which can be reversed by MEK inhibition. Thus, we could reclassify the variant from likely pathogenic to pathogenic using the American College of Medical Genetics (ACMG) criteria.


Asunto(s)
GTP Fosfohidrolasas , Proteínas de la Membrana , Enfermedades Mielodisplásicas-Mieloproliferativas , Pez Cebra , Animales , Preescolar , Femenino , Humanos , Masculino , Duplicación de Gen , GTP Fosfohidrolasas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de la Membrana/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Secuencias Repetidas en Tándem , Pez Cebra/genética
15.
Cell Rep ; 43(7): 114456, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38990722

RESUMEN

The rearrangement and expression of the immunoglobulin µ heavy chain (Igh) gene require communication of the intragenic Eµ and 3' regulatory region (RR) enhancers with the variable (VH) gene promoter. Eµ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eµ wild-type enhancer and that of Eµ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network. We found that MSL2 recruitment depends on YY1 and that gene knockout of Msl2 in primary pre-B cells reduces µ gene expression and chromatin looping of Eµ to the 3' RR enhancer and VH promoter. Moreover, Mof heterozygosity in mice impaired µ expression and early B cell differentiation. Together, these data suggest that the MSL/MOF complex regulates Igh gene expression by augmenting YY1-mediated enhancer-promoter communication.


Asunto(s)
Elementos de Facilitación Genéticos , Regiones Promotoras Genéticas , Factor de Transcripción YY1 , Animales , Masculino , Ratones , Diferenciación Celular , Elementos de Facilitación Genéticos/genética , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/metabolismo , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor de Transcripción YY1/metabolismo , Factor de Transcripción YY1/genética , Femenino
16.
Sci Signal ; 17(824): eadc9662, 2024 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-38377177

RESUMEN

The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.


Asunto(s)
Autoinmunidad , Linfocitos T CD8-positivos , Humanos , Masculino , Femenino , Ratones , Animales , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Autoinmunidad/genética , Linfocitos T CD8-positivos/metabolismo , Transducción de Señal , Inflamación , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo
17.
J Exp Med ; 220(1)2023 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-36350325

RESUMEN

Marginal zone (MZ) B cells represent innate-like B cells that mediate a fast immune response. The adhesion of MZ B cells to the marginal sinus of the spleen is governed by integrins. Here, we address the question of whether ß1-integrin has additional functions by analyzing Itgb1fl/flCD21Cre mice in which the ß1-integrin gene is deleted in mature B cells. We find that integrin ß1-deficient mice have a defect in the differentiation of MZ B cells and plasma cells. We show that integrin ß1-deficient transitional B cells, representing the precursors of MZ B cells, have enhanced B cell receptor (BCR) signaling, altered PI3K and Ras/ERK pathways, and an enhanced interaction of integrin-linked kinase (ILK) with the adaptor protein Grb2. Moreover, the MZ B cell defect of integrin ß1-deficient mice could, at least in part, be restored by a pharmacological inhibition of the PI3K pathway. Thus, ß1-integrin has an unexpected function in the differentiation and function of MZ B cells.


Asunto(s)
Integrina beta1 , Fosfatidilinositol 3-Quinasas , Ratones , Animales , Integrina beta1/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal , Diferenciación Celular , Integrinas
18.
Mech Dev ; 138 Pt 2: 97-112, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26259680

RESUMEN

Polycomb group (PcG) proteins regulate and maintain expression pattern of genes set early during development. Although originally isolated as regulators of homeotic genes, PcG members play a key role in epigenetic mechanisms that maintain the expression state of a large number of genes. All members of the two polycomb repressive complexes (PRC1 and PRC2) are conserved during evolution and while invertebrates generally have one gene for each of these, vertebrates have multiple homologues of them. It remains unclear, however, if different vertebrate PcG homologues have distinct or overlapping functions. We have identified and compared the sequence of PcG homologues in various organisms to analyze similarities and differences that shaped the evolutionary history of these proteins. Comparative analysis of the sequences led to the identification of several novel and signature motifs in the vertebrate homologues of these proteins, which can be directly used to pick respective homologues. Our analysis shows that PcG is an ancient gene group dating back to pre-bilaterian origin that has not only been conserved but also expanded during the evolution of complexity. The presence of unique motifs in each paralogue and its conservation for more than 500 Ma indicates their functional relevance and probable unique role. Although this does not rule out completely any overlapping function, our finding that these homologues only minimally overlap in their nuclear localization suggests that each PcG homologue has distinct function. We further propose distinct complex formation by the PcG members. Taken together, our studies suggest non-redundant and specific role of multiple homologues of PcG proteins in vertebrates and indicate major expansion event preceded by emergence of vertebrates that contributed as enhanced epigenetic resource to the evolution of complexity.


Asunto(s)
Genes Homeobox/genética , Proteínas del Grupo Polycomb/genética , Animales , Evolución Biológica , Línea Celular , Epigénesis Genética/genética , Células HEK293 , Humanos , Vertebrados/genética
19.
Gene ; 551(2): 167-75, 2014 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-25172211

RESUMEN

Simple sequence repeats (SSRs) or microsatellites are tandemly repeated short DNA sequence motifs found to be abundant in higher eukaryotes. Enrichment of SSRs with increasing genome complexity points to a positive selection and their functional relevance. We analyzed genomes of 24 organisms to find features that may help understand the functional relevance of SSRs. Of the 501 possible SSRs, only 73 show length specific enrichment. We also noticed that ~45 bp is the optimum length for a majority of them particularly in the human genome. Finally, we observed non-random distribution of ACG and CCG, enriched around transcriptional start sites (TSSs) in several species. Taken together, these results suggest that SSRs are functionally relevant with potential regulatory role. We propose that such repeats are evolving under positive selection pressure like any other functional element in the genome.


Asunto(s)
Regulación de la Expresión Génica , Genoma/genética , Repeticiones de Microsatélite/genética , Vertebrados/genética , Animales , Secuencia de Bases , Secuencia Conservada/genética , Bases de Datos de Ácidos Nucleicos , Exorribonucleasas , Humanos , Ratones , Pan troglodytes/genética , Ratas , Especificidad de la Especie , Sitio de Iniciación de la Transcripción , Repeticiones de Trinucleótidos/genética , Vertebrados/clasificación
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