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1.
Nat Immunol ; 21(12): 1574-1584, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33077975

RESUMO

A classical view of blood cell development is that multipotent hematopoietic stem and progenitor cells (HSPCs) become lineage-restricted at defined stages. Lin-c-Kit+Sca-1+Flt3+ cells, termed lymphoid-primed multipotent progenitors (LMPPs), have lost megakaryocyte and erythroid potential but are heterogeneous in their fate. Here, through single-cell RNA sequencing, we identify the expression of Dach1 and associated genes in this fraction as being coexpressed with myeloid/stem genes but inversely correlated with lymphoid genes. Through generation of Dach1-GFP reporter mice, we identify a transcriptionally and functionally unique Dach1-GFP- subpopulation within LMPPs with lymphoid potential with low to negligible classic myeloid potential. We term these 'lymphoid-primed progenitors' (LPPs). These findings define an early definitive branch point of lymphoid development in hematopoiesis and a means for prospective isolation of LPPs.


Assuntos
Biomarcadores , Proteínas do Olho/metabolismo , Genômica , Células Progenitoras Linfoides/metabolismo , Análise de Célula Única , Animais , Células Cultivadas , Biologia Computacional/métodos , Proteínas do Olho/genética , Perfilação da Expressão Gênica , Genômica/métodos , Hematopoese/genética , Sequenciamento de Nucleotídeos em Larga Escala , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteômica , Análise de Célula Única/métodos
3.
Cell ; 157(5): 1175-88, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24813849

RESUMO

Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.


Assuntos
Genes Letais , Hematopoese , Inflamação/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Animais Recém-Nascidos , Caspase 8/metabolismo , Morte Celular , Fígado/metabolismo , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fatores de Necrose Tumoral/metabolismo
4.
Nat Immunol ; 17(7): 816-24, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27213690

RESUMO

The detection of aberrant cells by natural killer (NK) cells is controlled by the integration of signals from activating and inhibitory ligands and from cytokines such as IL-15. We identified cytokine-inducible SH2-containing protein (CIS, encoded by Cish) as a critical negative regulator of IL-15 signaling in NK cells. Cish was rapidly induced in response to IL-15, and deletion of Cish rendered NK cells hypersensitive to IL-15, as evidenced by enhanced proliferation, survival, IFN-γ production and cytotoxicity toward tumors. This was associated with increased JAK-STAT signaling in NK cells in which Cish was deleted. Correspondingly, CIS interacted with the tyrosine kinase JAK1, inhibiting its enzymatic activity and targeting JAK for proteasomal degradation. Cish(-/-) mice were resistant to melanoma, prostate and breast cancer metastasis in vivo, and this was intrinsic to NK cell activity. Our data uncover a potent intracellular checkpoint in NK cell-mediated tumor immunity and suggest possibilities for new cancer immunotherapies directed at blocking CIS function.


Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Proliferação de Células/genética , Citotoxicidade Imunológica/genética , Vigilância Imunológica , Interferon gama/metabolismo , Interleucina-15/metabolismo , Janus Quinase 1/metabolismo , Ativação Linfocitária/genética , Melanoma Experimental , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , Neoplasias/imunologia , Transdução de Sinais/genética , Proteínas Supressoras da Sinalização de Citocina/genética
5.
Blood ; 141(26): 3199-3214, 2023 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-36928379

RESUMO

Polycythemia vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentrations, placing them at risk of life-threatening thrombotic events. Our genome-wide association study of 440 PV cases and 403 351 controls using UK Biobank data showed that single nucleotide polymorphisms in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed overrepresentation of homozygous HFE variants in patients with PV. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of mouse models of PV, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Furthermore, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130-coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.


Assuntos
Policitemia Vera , Animais , Camundongos , Policitemia Vera/genética , Policitemia Vera/complicações , Hepcidinas/genética , Estudo de Associação Genômica Ampla , Ferro/metabolismo , Fenótipo , Homeostase
6.
Immunity ; 45(3): 513-526, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27523270

RESUMO

The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8(-/-)Mlkl(-/-) and Fadd(-/-)Mlkl(-/-) mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease, and thrombocytopenia. These morbidities occurred more rapidly and with increased severity in Casp8(-/-)Mlkl(-/-) and Fadd(-/-)Mlkl(-/-) mice compared to Casp8(-/-)Ripk3(-/-) or Fadd(-/-)Ripk3(-/-) mice, respectively. These results demonstrate that MLKL is an essential effector of aberrant necroptosis in embryos caused by loss of Caspase-8 or FADD. Furthermore, they suggest that RIPK3 and/or MLKL may exert functions independently of necroptosis. It appears that non-necroptotic functions of RIPK3 contribute to the lymphadenopathy, autoimmunity, and excess cytokine production that occur when FADD or Caspase-8-mediated apoptosis is abrogated.


Assuntos
Apoptose/fisiologia , Doenças Autoimunes/metabolismo , Morte Celular/fisiologia , Proteína de Domínio de Morte Associada a Fas/metabolismo , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Caspase 8/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Necrose/metabolismo
7.
Immunity ; 44(1): 103-115, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795246

RESUMO

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.


Assuntos
Diferenciação Celular/imunologia , Proteína 2 Inibidora de Diferenciação/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Animais , Linhagem da Célula/imunologia , Células Cultivadas , Feminino , Citometria de Fluxo , Masculino , Camundongos , Camundongos Mutantes , Receptores de Interleucina-15/imunologia , Receptores de Interleucina-15/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo
9.
Blood ; 139(6): 845-858, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-34724565

RESUMO

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.


Assuntos
Autorrenovação Celular , Células-Tronco Hematopoéticas , Histona Acetiltransferases , Animais , Células Cultivadas , Senescência Celular , Deleção de Genes , Hematopoese , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Camundongos Endogâmicos C57BL
10.
Genes Dev ; 30(1): 78-91, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26728554

RESUMO

Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16(INK4a) and p19(ARF), which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Epigênese Genética , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/fisiopatologia , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Deleção de Genes , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Humanos , Leucemia Mieloide Aguda/genética , Camundongos , Camundongos Endogâmicos C57BL , Ligação Proteica , Fatores de Transcrição/genética
11.
Development ; 147(21)2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32994169

RESUMO

Börjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6-/Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.


Assuntos
Regulação para Baixo , Epilepsia/metabolismo , Face/anormalidades , Dedos/anormalidades , Transtornos do Crescimento/metabolismo , Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/metabolismo , Hipogonadismo/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Deficiência Intelectual Ligada ao Cromossomo X/metabolismo , Obesidade/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Epilepsia/sangue , Epilepsia/patologia , Face/patologia , Dedos/patologia , Transtornos do Crescimento/sangue , Transtornos do Crescimento/patologia , Hormônio do Crescimento/sangue , Hipogonadismo/sangue , Hipogonadismo/patologia , Hipotálamo/metabolismo , Fator de Crescimento Insulin-Like I/genética , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sistema Nervoso/metabolismo , Obesidade/sangue , Obesidade/patologia , Especificidade de Órgãos , Hipófise/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo
12.
Cytokine ; 165: 156167, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36934508

RESUMO

Suppressor Of Cytokine Signaling (SOCS) 1 is a critical negative regulator of cytokine signaling and required to protect against an excessive inflammatory response. Genetic deletion of Socs1 results in unrestrained cytokine signaling and neonatal lethality, characterised by an inflammatory immune infiltrate in multiple organs. Overexpression and structural studies have suggested that the SOCS1 kinase inhibitory region (KIR) and Src homology 2 (SH2) domain are important for interaction with and inhibition of the receptor-associated JAK1, JAK2 and TYK2 tyrosine kinases, which initiate downstream signaling. To investigate the role of the KIR and SH2 domain in SOCS1 function, we independently mutated key conserved residues in each domain and analysed the impact on cytokine signaling, and the in vivo impact on SOCS1 function. Mutation of the SOCS1-KIR or SH2 domain had no impact on the integrity of the SOCS box complex, however, mutation within the phosphotyrosine binding pocket of the SOCS1-SH2 domain specifically disrupted SOCS1 interaction with phosphorylated JAK1. In contrast, mutation of the KIR did not affect the interaction with JAK1, but did prevent SOCS1 inhibition of JAK1 autophosphorylation. In human and mouse cell lines, both mutants impacted the ability of SOCS1 to restrain cytokine signaling, and crucially, Socs1-R105A and Socs1-F59A mice displayed a neonatal lethality and excessive inflammatory phenotype similar to Socs1-null mice. This study defines a critical and non-redundant role for both the KIR and SH2 domain in endogenous SOCS1 function.


Assuntos
Citocinas , Proteína 1 Supressora da Sinalização de Citocina , Domínios de Homologia de src , Animais , Humanos , Camundongos , Citocinas/metabolismo , Fosforilação , Transdução de Sinais/fisiologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , TYK2 Quinase/metabolismo
13.
Immunity ; 39(3): 443-53, 2013 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-24012422

RESUMO

Mixed lineage kinase domain-like (MLKL) is a component of the "necrosome," the multiprotein complex that triggers tumor necrosis factor (TNF)-induced cell death by necroptosis. To define the specific role and molecular mechanism of MLKL action, we generated MLKL-deficient mice and solved the crystal structure of MLKL. Although MLKL-deficient mice were viable and displayed no hematopoietic anomalies or other obvious pathology, cells derived from these animals were resistant to TNF-induced necroptosis unless MLKL expression was restored. Structurally, MLKL comprises a four-helical bundle tethered to the pseudokinase domain, which contains an unusual pseudoactive site. Although the pseudokinase domain binds ATP, it is catalytically inactive and its essential nonenzymatic role in necroptotic signaling is induced by receptor-interacting serine-threonine kinase 3 (RIPK3)-mediated phosphorylation. Structure-guided mutation of the MLKL pseudoactive site resulted in constitutive, RIPK3-independent necroptosis, demonstrating that modification of MLKL is essential for propagation of the necroptosis pathway downstream of RIPK3.


Assuntos
Apoptose , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Fatores de Necrose Tumoral/metabolismo , Animais , Domínio Catalítico , Linhagem Celular , Cristalografia por Raios X , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fosfoproteínas Fosfatases , Monoéster Fosfórico Hidrolases/metabolismo , Fosforilação , Proteínas Quinases/química , Proteínas Quinases/genética , Transdução de Sinais
14.
Proteomics ; 21(11-12): e2000244, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945654

RESUMO

MARCH proteins are membrane-associated Ring-CH E3 ubiquitin ligases that dampen immune responses by downregulating cell surface expression of major histocompatibility complexes I and II as well as immune co-stimulatory receptors. We recently showed that MARCH2,3,4 and 9 also downregulate cell surface expression of the inflammatory cytokine receptor for interleukin-6 (IL6Rα). Here we use over-expression of these MARCH proteins in the M1 myeloid leukaemia cell line and cell surface proteomic analyses to globally analyse other potential targets of these proteins. A large range of cell surface proteins regulated by more than one MARCH protein in addition to several MARCH protein-specific cell surface targets were identified most of which were downregulated by MARCH expression. Prominent among these were several integrin complexes associated with immune cell homing, adhesion and migration. Integrin α4ß1 (VLA4 or VCAM-1 receptor) was downregulated only by MARCH2 and we showed that in MARCH2 knockout mice, Integrin α4 was upregulated specifically in mature B-lymphocytes and this was accompanied by decreased numbers of B-cells in the spleen.


Assuntos
Integrinas , Proteínas de Membrana/genética , Ubiquitina-Proteína Ligases/genética , Animais , Camundongos , Camundongos Knockout , Proteômica
15.
Blood ; 133(16): 1729-1741, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30755422

RESUMO

Somatically acquired mutations in PHF6 (plant homeodomain finger 6) frequently occur in hematopoietic malignancies and often coincide with ectopic expression of TLX3. However, there is no functional evidence to demonstrate whether these mutations contribute to tumorigenesis. Similarly, the role of PHF6 in hematopoiesis is unknown. We report here that Phf6 deletion in mice resulted in a reduced number of hematopoietic stem cells (HSCs), an increased number of hematopoietic progenitor cells, and an increased proportion of cycling stem and progenitor cells. Loss of PHF6 caused increased and sustained hematopoietic reconstitution in serial transplantation experiments. Interferon-stimulated gene expression was upregulated in the absence of PHF6 in hematopoietic stem and progenitor cells. The numbers of hematopoietic progenitor cells and cycling hematopoietic stem and progenitor cells were restored to normal by combined loss of PHF6 and the interferon α and ß receptor subunit 1. Ectopic expression of TLX3 alone caused partially penetrant leukemia. TLX3 expression and loss of PHF6 combined caused fully penetrant early-onset leukemia. Our data suggest that PHF6 is a hematopoietic tumor suppressor and is important for fine-tuning hematopoietic stem and progenitor cell homeostasis.


Assuntos
Células-Tronco Hematopoéticas/citologia , Proteínas de Homeodomínio/metabolismo , Leucemia/etiologia , Proteínas Repressoras/fisiologia , Animais , Carcinogênese , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Receptores de Interferon , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor
16.
Immunity ; 37(6): 1009-23, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23219391

RESUMO

Cytopenias are key prognostic indicators of life-threatening infection, contributing to immunosuppression and mortality. Here we define a role for Caspase-1-dependent death, known as pyroptosis, in infection-induced cytopenias by studying inflammasome activation in hematopoietic progenitor cells. The NLRP1a inflammasome is expressed in hematopoietic progenitor cells and its activation triggers their pyroptotic death. Active NLRP1a induced a lethal systemic inflammatory disease that was driven by Caspase-1 and IL-1ß but was independent of apoptosis-associated speck-like protein containing a CARD (ASC) and ameliorated by IL-18. Surprisingly, in the absence of IL-1ß-driven inflammation, active NLRP1a triggered pyroptosis of hematopoietic progenitor cells resulting in leukopenia at steady state. During periods of hematopoietic stress induced by chemotherapy or lymphocytic choriomeningitis virus (LCMV) infection, active NLRP1a caused prolonged cytopenia, bone marrow hypoplasia, and immunosuppression. Conversely, NLRP1-deficient mice showed enhanced recovery from chemotherapy and LCMV infection, demonstrating that NLRP1 acts as a cellular sentinel to alert Caspase-1 to hematopoietic and infectious stress.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Células-Tronco Hematopoéticas/metabolismo , Inflamassomos/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização CARD , Caspase 1/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Dermatite/imunologia , Dermatite/metabolismo , Fluoruracila/farmacologia , Hematopoese/efeitos dos fármacos , Hematopoese/imunologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/virologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Camundongos , Camundongos Knockout , Mutação , Pancitopenia/imunologia , Pancitopenia/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
17.
PLoS Biol ; 16(8): e2004986, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30080881

RESUMO

Distinct transcriptional states are maintained through organization of chromatin, resulting from the sum of numerous repressive and active histone modifications, into tightly packaged heterochromatin versus more accessible euchromatin. Polycomb repressive complex 2 (PRC2) is the main mammalian complex responsible for histone 3 lysine 27 trimethylation (H3K27me3) and is integral to chromatin organization. Using in vitro and in vivo studies, we show that deletion of Suz12, a core component of all PRC2 complexes, results in loss of H3K27me3 and H3K27 dimethylation (H3K27me2), completely blocks normal mammary gland development, and profoundly curtails progenitor activity in 3D organoid cultures. Through the application of mammary organoids to bypass the severe phenotype associated with Suz12 loss in vivo, we have explored gene expression and chromatin structure in wild-type and Suz12-deleted basal-derived organoids. Analysis of organoids led to the identification of lineage-specific changes in gene expression and chromatin structure, inferring cell type-specific PRC2-mediated gene silencing of the chromatin state. These expression changes were accompanied by cell cycle arrest but not lineage infidelity. Together, these data indicate that canonical PRC2 function is essential for development of the mammary gland through the repression of alternate transcription programs and maintenance of chromatin states.


Assuntos
Glândulas Mamárias Animais/embriologia , Complexo Repressor Polycomb 2/fisiologia , Animais , Cromatina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Feminino , Heterocromatina/metabolismo , Código das Histonas , Histonas/metabolismo , Lisina/metabolismo , Glândulas Mamárias Animais/metabolismo , Metilação , Camundongos , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas do Grupo Polycomb , Cultura Primária de Células , Processamento de Proteína Pós-Traducional
18.
Nucleic Acids Res ; 47(D1): D780-D785, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30395284

RESUMO

During haematopoiesis, haematopoietic stem cells differentiate into restricted potential progenitors before maturing into the many lineages required for oxygen transport, wound healing and immune response. We have updated Haemopedia, a database of gene-expression profiles from a broad spectrum of haematopoietic cells, to include RNA-seq gene-expression data from both mice and humans. The Haemopedia RNA-seq data set covers a wide range of lineages and progenitors, with 57 mouse blood cell types (flow sorted populations from healthy mice) and 12 human blood cell types. This data set has been made accessible for exploration and analysis, to researchers and clinicians with limited bioinformatics experience, on our online portal Haemosphere: https://www.haemosphere.org. Haemosphere also includes nine other publicly available high-quality data sets relevant to haematopoiesis. We have added the ability to compare gene expression across data sets and species by curating data sets with shared lineage designations or to view expression gene vs gene, with all plots available for download by the user.


Assuntos
Bases de Dados Genéticas , Expressão Gênica/genética , Hematopoese/genética , Transcriptoma/genética , Animais , Biologia Computacional , Células-Tronco Hematopoéticas/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Camundongos , RNA-Seq , Software
19.
Nat Immunol ; 9(7): 810-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18500345

RESUMO

Ets-related gene (ERG), which encodes a member of the Ets family of transcription factors, is a potent oncogene. Chromosomal rearrangements involving ERG are found in acute myeloid leukemia, acute lymphoblastic leukemia, Ewing's sarcoma and more than half of all prostate cancers; however, the normal physiological function of Erg is unknown. We did a sensitized genetic screen of the mouse for regulators of hematopoietic stem cell function and report here a germline mutation of Erg. We show that Erg is required for definitive hematopoiesis, adult hematopoietic stem cell function and the maintenance of normal peripheral blood platelet numbers.


Assuntos
Hematopoese/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Transativadores/genética , Transativadores/metabolismo , Animais , Citometria de Fluxo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Mutantes , Mutação , Transcrição Gênica , Regulador Transcricional ERG
20.
Blood ; 132(14): 1526-1534, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30049810

RESUMO

The tendency of 5-methylcytosine (5mC) to undergo spontaneous deamination has had a major role in shaping the human genome, and this methylation damage remains the primary source of somatic mutations that accumulate with age. How 5mC deamination contributes to cancer risk in different tissues remains unclear. Genomic profiling of 3 early-onset acute myeloid leukemias (AMLs) identified germ line loss of MBD4 as an initiator of 5mC-dependent hypermutation. MBD4-deficient AMLs display a 33-fold higher mutation burden than AML generally, with >95% being C>T in the context of a CG dinucleotide. This distinctive signature was also observed in sporadic cancers that acquired biallelic mutations in MBD4 and in Mbd4 knockout mice. Sequential sampling of germ line cases demonstrated repeated expansion of blood cell progenitors with pathogenic mutations in DNMT3A, a key driver gene for both clonal hematopoiesis and AML. Our findings reveal genetic and epigenetic factors that shape the mutagenic influence of 5mC. Within blood cells, this links methylation damage to the driver landscape of clonal hematopoiesis and reveals a conserved path to leukemia. Germ line MBD4 deficiency enhances cancer susceptibility and predisposes to AML.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Endodesoxirribonucleases/genética , Regulação Leucêmica da Expressão Gênica , Hematopoese , Leucemia Mieloide Aguda/genética , Adulto , DNA Metiltransferase 3A , Feminino , Deleção de Genes , Células Germinativas/metabolismo , Células Germinativas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Mutação , Acúmulo de Mutações
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