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1.
J Cell Physiol ; 235(5): 4279-4290, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31612516

RESUMO

Signaling pathways transmit extracellular cues into cells and regulate transcriptome and epigenome to maintain or change the cell identity. Protein kinases and phosphatases are critical for signaling transduction and regulation. Here, we report that CDK11, a member of the CDK family, is required for the maintenance of human embryonic stem cell (hESC) self-renewal. Our results show that, among the three main isoforms of CDK11, CDK11p46 is the main isoform safeguarding the hESC identity. Mechanistically, CDK11 constrains two important mitogen-activated protein kinase (MAPK) signaling pathways (JNK and p38 signaling) through modulating the activity of protein phosphatase 1. Furthermore, CDK11 knockdown activates transforming growth factor ß (TGF-ß)/SMAD2/3 signaling and upregulates certain nonneural differentiation-associated genes. Taken together, this study uncovers a kinase required for hESC self-renewal through fine-tuning MAPK and TGF-ß signaling at appropriate levels. The kinase-phosphatase axis reported here may shed new light on the molecular mechanism sustaining the identity of hESCs.

2.
Stem Cell Reports ; 13(6): 1038-1052, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31761677

RESUMO

The generation of brain region-specific progenitors from human embryonic stem cells (hESCs) is critical for their application. However, transcriptional regulation of neural regionalization in humans is poorly understood. Here, we applied a rostrocaudal patterning system from hESCs to dissect global transcriptional networks controlling early neural regionalization. We found that SOX21 is required for rostral forebrain fate specification. SOX21 knockout led to activation of Wnt signaling, resulting in caudalization of regional identity of rostral forebrain neural progenitor cells. Moreover, we identified WNT8B as a SOX21 direct target. Deletion of WNT8B or inhibition of Wnt signaling in SOX21 knockout neural progenitor cells restored rostral forebrain identity. Furthermore, SOX21 interacted with ß-catenin, interfering with the binding of TCF4/ß-catenin complex to the WNT8B enhancer. Collectively, these results unveil the unknown role of SOX21 and shed light on how a transcriptional factor modulates early neural regionalization through crosstalk with a key component of Wnt signaling.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31438503

RESUMO

Climate change has made countries around the world realize the importance of reducing carbon emissions. Reductions in carbon emissions needs the support of policy, technology, and financial capital. The single/double/three-threshold model is used here with data from China to study the different impact of financial development in carbon emissions in high-energy industries when the threshold variables are in different intervals. The results show that when loan size is the core explanatory variable, and research and development (R and D) expenditure and energy structure are the threshold variables, the loan size variable has a significant effect on emission reductions in high-energy industries, and this effect is strengthened with increases in R and D expenditure and decreases in the proportion of energy from coal. Taking energy intensity as the threshold variable, the relationship between loan size and carbon dioxide emissions is V-shaped. With economic structure as the threshold variable, loan size has a significant effect on emissions reduction when the proportion of industrial added value in high-energy industries is low. When using foreign investment as the core explanatory variable, R and D expenditure, energy consumption intensity, and industrial structure are threshold variables. The impact of foreign investment on carbon dioxide emissions is negative, but when the threshold variable is within different intervals, this negative impact differs. With stock market value as the core explanatory variable, and R and D expenditure and energy structure as the threshold variables, the stock market value can promote reductions in carbon emissions, but when R and D expenditure and the proportion of coal consumption is high, stock market value has no significant effect on emissions reduction. When energy consumption intensity is the threshold variable, the relationship between stock market value and carbon dioxide emissions is V-shaped.


Assuntos
Poluição do Ar/prevenção & controle , Dióxido de Carbono , Desenvolvimento Econômico , Indústrias/economia , Tecnologia/economia , Poluição do Ar/economia , China , Mudança Climática , Carvão Mineral , Eletricidade , Gastos em Saúde , Internacionalidade , Investimentos em Saúde
4.
Artigo em Inglês | MEDLINE | ID: mdl-31100968

RESUMO

The spatial autocorrelation analysis method was applied to panel data from the provinces of China (including autonomous regions and municipalities directly under the central government) for the period 2003 to 2016 in order to construct a spatial Durbin model of technological progress and financial support in relation to reductions in carbon emissions. The results show that China's carbon intensity presents significant spatial spillover effects under different spatial weights, which indicates that the carbon intensity of a province is influenced not only by its own characteristics, but also by the carbon emission behaviors of geographically adjacent and economically similar provinces and regions. Financial structure, financial scale, and financial efficiency all have significant effects on carbon intensity within a province, while financial structure is also linked to carbon intensity in other regions, but financial scale has no significant spillover effect on carbon intensity in space. Areas with high financial efficiency can reduce their own carbon intensity as well as that of surrounding areas. The inter-regional spillover effect of technological progress on carbon intensity is stronger than the spillover effect, but there is a time lag.


Assuntos
Carbono , Apoio Financeiro , Tecnologia , Dióxido de Carbono , China , Cidades , Análise Espacial
5.
J Biol Chem ; 294(25): 9959-9972, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31092598

RESUMO

Mesoderm development is a finely tuned process initiated by the differentiation of pluripotent epiblast cells. Serine/threonine kinase 40 (STK40) controls the development of several mesoderm-derived cell types, its overexpression induces differentiation of mouse embryonic stem cells (mESCs) toward the extraembryonic endoderm, and Stk40 knockout (KO) results in multiple organ failure and is lethal at the perinatal stage in mice. However, molecular mechanisms underlying the physiological functions of STK40 in mesoderm differentiation remain elusive. Here, we report that Stk40 ablation impairs mesoderm differentiation both in vitro and in vivo Mechanistically, STK40 interacts with both the E3 ubiquitin ligase mammalian constitutive photomorphogenesis protein 1 (COP1) and the transcriptional regulator proto-oncogene c-Jun (c-JUN), promoting c-JUN protein degradation. Consequently, Stk40 knockout leads to c-JUN protein accumulation, which, in turn, apparently suppresses WNT signaling activity and impairs the mesoderm differentiation process. Overall, this study reveals that STK40, together with COP1, represents a previously unknown regulatory axis that modulates the c-JUN protein level within an appropriate range during mesoderm differentiation from mESCs. Our findings provide critical insights into the molecular mechanisms regulating the c-JUN protein level and may have potential implications for managing cellular disorders arising from c-JUN dysfunction.

6.
Cell Death Dis ; 9(9): 924, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30206204

RESUMO

Trophoblast lineages, precursors of the placenta, are essential for post-implantation embryo survival. However, the regulatory network of trophoblast development remains incompletely understood. Here, we report that Cited1, a transcription coactivator, is a robust inducer for trophoblast-like state from mouse embryonic stem cells (ESCs). Depletion of Cited1 in ESCs compromises the trophoblast lineage specification induced by BMP signaling. In contrast, overexpression of Cited1 in ESCs induces a trophoblast-like state with elevated expression of trophoblast marker genes in vitro and generation of trophoblastic tumors in vivo. Furthermore, global transcriptome profile analysis indicates that ectopic Cited1 activates a trophoblast-like transcriptional program in ESCs. Mechanistically, Cited1 interacts with Bmpr2 and Smad4 to activate the Cited1-Bmpr2-Smad1/5/8 axis in the cytoplasm and Cited1-Smad4-p300 complexes in the nucleus, respectively. Collectively, our results show that Cited1 plays an important role in regulating trophoblast lineage specification through activating the BMP signaling pathway.


Assuntos
Proteína Morfogenética Óssea 1/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Embrionárias Murinas/citologia , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Trofoblastos/citologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Linhagem Celular , Proteína p300 Associada a E1A/metabolismo , Feminino , Camundongos , Proteínas Nucleares/genética , Placenta/embriologia , Gravidez , Transdução de Sinais , Proteína Smad4/metabolismo , Transativadores/genética , Transcrição Genética/genética
7.
Cell Death Dis ; 8(3): e2722, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28358362

RESUMO

The serine threonine kinase Stk40 has been shown to involve in mouse embryonic stem cell differentiation, pulmonary maturation and adipocyte differentiation. Here we report that targeted deletion of Stk40 leads to fetal liver hypoplasia and anemia in the mouse embryo. The reduction of erythrocytes in the fetal liver is accompanied by increased apoptosis and compromised erythroid maturation. Stk40-/- fetal liver cells have significantly reduced colony-forming units (CFUs) capable of erythroid differentiation, including burst forming unit-erythroid, CFU-erythroid (CFU-E), and CFU-granulocyte, erythrocyte, megakaryocyte and macrophage, but not CFU-granulocyte/macrophages. Purified Stk40-/- megakaryocyte-erythrocyte progenitors produce substantially fewer CFU-E colonies compared to control cells. Moreover, Stk40-/- fetal liver erythroblasts fail to form normal erythroblastic islands in association with wild type or Stk40-/- macrophages, indicating an intrinsic defect of Stk40-/- erythroblasts. Furthermore, the hematopoietic stem and progenitor cell pool is reduced in Stk40-/- fetal livers but still retains the multi-lineage reconstitution capacity. Finally, comparison of microarray data between wild type and Stk40-/- E14.5 fetal liver cells reveals a potential role of aberrantly activated TNF-α signaling in Stk40 depletion induced dyserythropoiesis with a concomitant increase in cleaved caspase-3 and decrease in Gata1 proteins. Altogether, the identification of Stk40 as a regulator for fetal erythroid maturation and survival provides new clues to the molecular regulation of erythropoiesis and related diseases.


Assuntos
Eritroblastos/metabolismo , Eritropoese/fisiologia , Feto/embriologia , Fígado/embriologia , Células Progenitoras de Megacariócitos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Deleção de Genes , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/genética
8.
J Biol Chem ; 292(23): 9840-9854, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28298438

RESUMO

The mammalian post-implantation embryo has been extensively investigated at the tissue level. However, to unravel the molecular basis for the cell-fate plasticity and determination, it is essential to study the characteristics of individual cells. In particular, the individual definitive endoderm (DE) cells have not been characterized in vivo Here, we report gene expression patterns in single cells freshly isolated from mouse embryos on days 5.5 and 6.5. Initial transcriptome data from 124 single cells yielded signature genes for the epiblast, visceral endoderm, and extra-embryonic ectoderm and revealed a unique distribution pattern of fibroblast growth factor (FGF) ligands and receptors. Further analysis indicated that early-stage epiblast cells do not segregate into lineages of the major germ layers. Instead, some cells began to diverge from epiblast cells, displaying molecular features of the premesendoderm by expressing higher levels of mesendoderm markers and lower levels of Sox3 transcripts. Analysis of single-cell high-throughput quantitative RT-PCR data from 441 cells identified a late stage of the day 6.5 embryo in which mesoderm and DE cells emerge, with many of them coexpressing Oct4 and Gata6 Analysis of single-cell RNA-sequence data from 112 cells of the late-stage day 6.5 embryos revealed differentially expressed signaling genes and networks of transcription factors that might underlie the segregation of the mesoderm and DE lineages. Moreover, we discovered a subpopulation of mesoderm cells that possess molecular features of the extraembryonic mesoderm. This study provides fundamental insight into the molecular basis for lineage segregation in post-implantation mouse embryos.


Assuntos
Antígenos de Diferenciação/biossíntese , Linhagem da Célula/fisiologia , Embrião de Mamíferos , Desenvolvimento Embrionário/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Transcriptoma/fisiologia , Animais , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fator de Transcrição GATA6/biossíntese , Camundongos , Fator 3 de Transcrição de Octâmero/biossíntese , Fatores de Transcrição SOXB1/biossíntese
9.
J Cell Physiol ; 228(7): 1443-51, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23255053

RESUMO

Itch, a C2-WW-HECT domain ubiquitin E3 ligase, plays an important role in various biological processes. However, its role in embryonic stem cells (ESCs) remains unknown. Here, we report that Itch interacts with and targets pluripotency-associated transcription factor Oct4 for ubiquitination. Moreover, Itch enhances Oct4 transcriptional activities and controls Oct4 protein stability dependent on its catalytic activity. Importantly, silencing Itch expression compromises ESC self-renewal capacity and somatic cell reprogramming efficiency. Taken together, our study identifies Itch as a regulator of Oct4 stability and transcriptional activity, establishing a functional link between an E3 ligase and the regulation of pluripotency.


Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas Repressoras/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Desdiferenciação Celular , Linhagem Celular , Proliferação de Células , Células-Tronco de Carcinoma Embrionário , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Camundongos , Fator 3 de Transcrição de Octâmero/genética , Estabilidade Proteica , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
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