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1.
Nat Immunol ; 19(9): 932-941, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30127433

RESUMEN

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular/genética , Autorrenovación de las Células/genética , Proteínas Cromosómicas no Histona/metabolismo , Células Madre Hematopoyéticas/fisiología , Leucemia Mieloide Aguda/genética , Macrófagos/fisiología , Proteínas Nucleares/genética , Fosfoproteínas/genética , Animales , Proteínas de Ciclo Celular/genética , Células Cultivadas , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inflamación/genética , Lipopolisacáridos/inmunología , Ratones , Ratones Noqueados , Mutación/genética , Cohesinas
2.
FASEB J ; 29(2): 455-63, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25376832

RESUMEN

Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis.


Asunto(s)
Linfocitos B/citología , Suspensión Trasera/fisiología , Linfopoyesis/fisiología , Vuelo Espacial , Corticoesteroides/metabolismo , Envejecimiento , Animales , Células de la Médula Ósea/citología , Remodelación Ósea , Diferenciación Celular , Linaje de la Célula , Citocinas/metabolismo , Células Madre Hematopoyéticas/citología , Inmunoglobulinas/metabolismo , Interleucina-7/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Factor de Transcripción PAX5/metabolismo , Factor de Transcripción STAT5/metabolismo , Células Madre , Factores de Tiempo , Transactivadores/metabolismo , Microtomografía por Rayos X
3.
Nat Struct Mol Biol ; 30(4): 489-501, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36941433

RESUMEN

Recent studies have shown that repressive chromatin machinery, including DNA methyltransferases and polycomb repressor complexes, binds to chromosomes throughout mitosis and their depletion results in increased chromosome size. In the present study, we show that enzymes that catalyze H3K9 methylation, such as Suv39h1, Suv39h2, G9a and Glp, are also retained on mitotic chromosomes. Surprisingly, however, mutants lacking histone 3 lysine 9 trimethylation (H3K9me3) have unusually small and compact mitotic chromosomes associated with increased histone H3 phospho Ser10 (H3S10ph) and H3K27me3 levels. Chromosome size and centromere compaction in these mutants were rescued by providing exogenous first protein lysine methyltransferase Suv39h1 or inhibiting Ezh2 activity. Quantitative proteomic comparisons of native mitotic chromosomes isolated from wild-type versus Suv39h1/Suv39h2 double-null mouse embryonic stem cells revealed that H3K9me3 was essential for the efficient retention of bookmarking factors such as Esrrb. These results highlight an unexpected role for repressive heterochromatin domains in preserving transcription factor binding through mitosis and underscore the importance of H3K9me3 for sustaining chromosome architecture and epigenetic memory during cell division.


Asunto(s)
Proteómica , Factores de Transcripción , Animales , Ratones , Factores de Transcripción/metabolismo , Histonas/metabolismo , Heterocromatina , Metilación de ADN , Mitosis , Proteínas del Grupo Polycomb/genética , Metiltransferasas/metabolismo
4.
Nat Commun ; 11(1): 4118, 2020 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-32807789

RESUMEN

Epigenetic information is transmitted from mother to daughter cells through mitosis. Here, to identify factors that might play a role in conveying epigenetic memory through cell division, we report on the isolation of unfixed, native chromosomes from metaphase-arrested cells using flow cytometry and perform LC-MS/MS to identify chromosome-bound proteins. A quantitative proteomic comparison between metaphase-arrested cell lysates and chromosome-sorted samples reveals a cohort of proteins that were significantly enriched on mitotic ESC chromosomes. These include pluripotency-associated transcription factors, repressive chromatin-modifiers such as PRC2 and DNA methyl-transferases, and proteins governing chromosome architecture. Deletion of PRC2, Dnmt1/3a/3b or Mecp2 in ESCs leads to an increase in the size of individual mitotic chromosomes, consistent with de-condensation. Similar results were obtained by the experimental cleavage of cohesin. Thus, we identify chromosome-bound factors in pluripotent stem cells during mitosis and reveal that PRC2, DNA methylation and Mecp2 are required to maintain chromosome compaction.


Asunto(s)
Cromatina/metabolismo , Cromosomas/metabolismo , Células Madre Embrionarias/metabolismo , Factores de Transcripción/metabolismo , Animales , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/genética , Metilación de ADN/fisiología , ADN Metiltransferasa 3A , Técnica del Anticuerpo Fluorescente , Proteína 2 de Unión a Metil-CpG/metabolismo , Ratones , Proteómica , ADN Metiltransferasa 3B
5.
Stem Cell Reports ; 6(6): 970-984, 2016 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-27304919

RESUMEN

The capacity of hematopoietic stem cells (HSC) to generate B lymphocytes declines with age, contributing to impaired immune function in the elderly. Here we show that the histone methyltransferase SUV39H1 plays an important role in human B lymphoid differentiation and that expression of SUV39H1 decreases with age in both human and mouse HSC, leading to a global reduction in H3K9 trimethylation and perturbed heterochromatin function. Further, we demonstrate that SUV39H1 is a target of microRNA miR-125b, a known regulator of HSC function, and that expression of miR-125b increases with age in human HSC. Overexpression of miR-125b and inhibition of SUV39H1 in young HSC induced loss of B cell potential. Conversely, both inhibition of miR-125 and enforced expression of SUV39H1 improved the capacity of HSC from elderly individuals to generate B cells. Our findings highlight the importance of heterochromatin regulation in HSC aging and B lymphopoiesis.


Asunto(s)
Envejecimiento/inmunología , Linfocitos B/citología , Células Madre Hematopoyéticas/citología , Linfopoyesis/inmunología , Metiltransferasas/genética , MicroARNs/genética , Proteínas Represoras/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Animales , Antagomirs/genética , Antagomirs/metabolismo , Linfocitos B/inmunología , Secuencia de Bases , Diferenciación Celular , Femenino , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/inmunología , Heterocromatina/química , Heterocromatina/metabolismo , Humanos , Linfopoyesis/genética , Masculino , Metiltransferasas/inmunología , Ratones , MicroARNs/antagonistas & inhibidores , MicroARNs/inmunología , Cultivo Primario de Células , Proteínas Represoras/inmunología , Transducción de Señal
6.
PLoS One ; 6(11): e27283, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22076146

RESUMEN

Apoptosis Inducing Factor (AIF) is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal and cardiomyocyte apoptosis induced by oxidative stress. Conversely in vitro, AIF has been demonstrated to have a pro-apoptotic role upon induction of the mitochondrial death pathway, once AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation. Given that the aif hypomorphic harlequin (Hq) mutant mouse model displays severe sarcopenia, we examined skeletal muscle from the aif hypomorphic mice in more detail. Adult AIF-deficient skeletal myofibers display oxidative stress and a severe form of atrophy, associated with a loss of myonuclei and a fast to slow fiber type switch, both in "slow" muscles such as soleus, as well as in "fast" muscles such as extensor digitorum longus, most likely resulting from an increase of MEF2 activity. This fiber type switch was conserved in regenerated soleus and EDL muscles of Hq mice subjected to cardiotoxin injection. In addition, muscle regeneration in soleus and EDL muscles of Hq mice was severely delayed. Freshly cultured myofibers, soleus and EDL muscle sections from Hq mice displayed a decreased satellite cell pool, which could be rescued by pretreating aif hypomorphic mice with the manganese-salen free radical scavenger EUK-8. Satellite cell activation seems to be abnormally long in Hq primary culture compared to controls. However, AIF deficiency did not affect myoblast cell proliferation and differentiation. Thus, AIF protects skeletal muscles against oxidative stress-induced damage probably by protecting satellite cells against oxidative stress and maintaining skeletal muscle stem cell number and activation.


Asunto(s)
Factor Inductor de la Apoptosis/fisiología , Apoptosis , Fibras Musculares Esqueléticas/fisiología , Estrés Oxidativo , Animales , Antioxidantes/farmacología , Enfermedades del Sistema Nervioso Autónomo , Western Blotting , Recuento de Células , Diferenciación Celular , Fragmentación del ADN , Etilenodiaminas/farmacología , Técnica del Anticuerpo Fluorescente , Rubor , Hipohidrosis , Técnicas para Inmunoenzimas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Mutantes , Mitocondrias/efectos de los fármacos , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Compuestos Organometálicos/farmacología , Fenotipo , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa
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