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1.
Cell ; 163(1): 230-45, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26365490

RESUMO

Embryonic stem cells (ESCs) repress the expression of exogenous proviruses and endogenous retroviruses (ERVs). Here, we systematically dissected the cellular factors involved in provirus repression in embryonic carcinomas (ECs) and ESCs by a genome-wide siRNA screen. Histone chaperones (Chaf1a/b), sumoylation factors (Sumo2/Ube2i/Sae1/Uba2/Senp6), and chromatin modifiers (Trim28/Eset/Atf7ip) are key determinants that establish provirus silencing. RNA-seq analysis uncovered the roles of Chaf1a/b and sumoylation modifiers in the repression of ERVs. ChIP-seq analysis demonstrates direct recruitment of Chaf1a and Sumo2 to ERVs. Chaf1a reinforces transcriptional repression via its interaction with members of the NuRD complex (Kdm1a, Hdac1/2) and Eset, while Sumo2 orchestrates the provirus repressive function of the canonical Zfp809/Trim28/Eset machinery by sumoylation of Trim28. Our study reports a genome-wide atlas of functional nodes that mediate proviral silencing in ESCs and illuminates the comprehensive, interconnected, and multi-layered genetic and epigenetic mechanisms by which ESCs repress retroviruses within the genome.


Assuntos
Células-Tronco Embrionárias/virologia , Retrovirus Endógenos/genética , Provírus/genética , Animais , Fator 1 de Modelagem da Cromatina/genética , Fator 1 de Modelagem da Cromatina/metabolismo , Células-Tronco de Carcinoma Embrionário/virologia , Epigênese Genética , Camundongos , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo
2.
Proc Natl Acad Sci U S A ; 109(7): 2521-6, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-22308476

RESUMO

The boronic acid dipeptide bortezomib inhibits the chymotrypsin-like activity of the 26S proteasome and shows significant therapeutic efficacy in multiple myeloma. However, recent studies suggest that bortezomib may have more complex mechanisms of action in treating cancer. We report here that the endocytosis and lysosomal degradation of the receptor tyrosine kinase C-KIT are required for bortezomib- but not tyrosine kinase inhibitor imatinib-caused apoptosis of t(8;21) leukemia and gastrointestinal stromal tumor cells, suggesting that C-KIT may recruit an apoptosis initiator. We show that C-KIT binds and phosphorylates heat shock protein 90ß (Hsp90ß), which sequestrates apoptotic protease activating factor 1 (Apaf-1). Bortezomib dephosphorylates pHsp90ß and releases Apaf-1. Although the activated caspase-3 is not sufficient to cause marked apoptosis, it cleaves the t(8;21) generated acute myeloid leukemia 1-eight twenty one (AML1-ETO) and AML1-ETO9a fusion proteins, with production of cleavage fragments that perturb the functions of the parental oncoproteins and further contribute to apoptosis. Notably, bortezomib exerts potent therapeutic efficacy in mice bearing AML1-ETO9a-driven leukemia. These data show that C-KIT-pHsp90ß-Apaf-1 cascade is critical for some malignant cells to evade apoptosis, and the clinical therapeutic potentials of bortezomib in C-KIT-driven neoplasms should be further explored.


Assuntos
Ácidos Borônicos/farmacologia , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Leucemia/patologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirazinas/farmacologia , Translocação Genética , Apoptose , Bortezomib , Humanos , Leucemia/genética , Fosforilação , Ligação Proteica
3.
Stem Cell Reports ; 14(2): 210-225, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32004493

RESUMO

The effects of ascorbate on adult cell fate specification remain largely unknown. Using our stepwise and chemically defined system to derive lateral mesoderm progenitors from human pluripotent stem cells (hPSCs), we found that ascorbate increased the expression of mesenchymal stromal cell (MSC) markers, purity of MSCs, the long-term self-renewal and osteochondrogenic capacity of hPSC-MSCs in vitro. Moreover, ascorbate promoted MSC specification in an iron-dependent fashion, but not in a redox-dependent manner. Further studies revealed that iron synergized with ascorbate to regulate hPSC-MSC histone methylation, promote their long-term self-renewal, and increase their osteochondrogenic capacity. We found that one of the histone demethylases affected by ascorbate, KDM4B, was necessary to promote the specification of hPSC-MSCs. This mechanistic understanding led to the metabolic optimization of hPSC-MSCs with an extended lifespan in vitro and the ability to fully repair cartilage defects upon transplantation in vivo. Our results highlight the importance of ascorbate and iron metabolism in adult human cell fate specification.


Assuntos
Ácido Ascórbico/farmacologia , Osso e Ossos/citologia , Autorrenovação Celular/efeitos dos fármacos , Ferro/farmacologia , Células-Tronco Mesenquimais/citologia , Ativinas/metabolismo , Proteína Morfogenética Óssea 4/metabolismo , Cartilagem/patologia , Células Cultivadas , Humanos , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Mesoderma/citologia , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Linha Primitiva/citologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Proteínas Wnt/metabolismo , Cicatrização/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo
4.
Nat Commun ; 9(1): 1537, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29670118

RESUMO

H3.3 is a histone variant, which is deposited on genebodies and regulatory elements, by Hira, marking active transcription. Moreover, H3.3 is deposited on heterochromatin by Atrx/Daxx complex. The exact role of H3.3 in cell fate transition remains elusive. Here, we investigate the dynamic changes in the deposition of the histone variant H3.3 during cellular reprogramming. H3.3 maintains the identities of the parental cells during reprogramming as its removal at early time-point enhances the efficiency of the process. We find that H3.3 plays a similar role in transdifferentiation to hematopoietic progenitors and neuronal differentiation from embryonic stem cells. Contrastingly, H3.3 deposition on genes associated with the newly reprogrammed lineage is essential as its depletion at the later phase abolishes the process. Mechanistically, H3.3 deposition by Hira, and its K4 and K36 modifications are central to the role of H3.3 in cell fate conversion. Finally, H3.3 safeguards fibroblast lineage by regulating Mapk cascade and collagen synthesis.


Assuntos
Linhagem da Célula , Chaperonas de Histonas/metabolismo , Histonas/química , Células-Tronco Pluripotentes/citologia , Animais , Diferenciação Celular , Imunoprecipitação da Cromatina , Colágeno/química , Fibroblastos/metabolismo , Células HEK293 , Heterocromatina , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Neurônios/metabolismo , Nucleossomos , Ligação Proteica , Retroviridae/genética , Software , Transcriptoma
5.
Nat Commun ; 7: 13396, 2016 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-27869129

RESUMO

Recent efforts have attempted to convert non-blood cells into hematopoietic stem cells (HSCs) with the goal of generating blood lineages de novo. Here we show that hematopoietic transcription factors Scl, Lmo2, Runx1 and Bmi1 can convert a developmentally distant lineage (fibroblasts) into 'induced hematopoietic progenitors' (iHPs). Functionally, iHPs generate acetylcholinesterase+ megakaryocytes and phagocytic myeloid cells in vitro and can also engraft immunodeficient mice, generating myeloerythoid and B-lymphoid cells for up to 4 months in vivo. Molecularly, iHPs transcriptionally resemble native Kit+ hematopoietic progenitors. Mechanistically, reprogramming factor Lmo2 implements a hematopoietic programme in fibroblasts by rapidly binding to and upregulating the Hhex and Gfi1 genes within days. Moreover the reprogramming transcription factors also require extracellular BMP and MEK signalling to cooperatively effectuate reprogramming. Thus, the transcription factors that orchestrate embryonic hematopoiesis can artificially reconstitute this programme in developmentally distant fibroblasts, converting them into engraftable blood progenitors.


Assuntos
Reprogramação Celular , Fibroblastos/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Fatores de Transcrição/fisiologia , Acetilcolinesterase/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , MAP Quinases Reguladas por Sinal Extracelular , Regulação da Expressão Gênica , Genômica , Humanos , Megacariócitos/fisiologia , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno , Células Mieloides/fisiologia , Fagócitos/fisiologia , Análise Serial de Proteínas , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Leuk Res ; 35(2): 214-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20691473

RESUMO

Triptolide is a compound isolated from the traditional Chinese medicinal herb Tripterygium wilfordii that shows potent anti-tumor activities, but its effects on acute myeloid leukemia with t(8;21) remain unclear. Here we report that triptolide inhibits cell proliferation and induces apoptosis in a dose- and time-dependent manner of t(8;21)-bearing Kasumi-1, SKNO-1 and CD34+ cells harvested from bone marrow samples of patients with t(8;21) leukemia. We show that triptolide triggers cleavage of the resultant AML1-ETO fusion protein of t(8;21), and causes downregulation of C-KIT followed by inhibition of JAK-STAT signaling. Triptolide downregulates p65 and inhibits the DNA-binding activity of NF-κB. Our data indicate that triptolide might be an effective agent for t(8;21) leukemia.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Diterpenos/farmacologia , Leucemia Mieloide Aguda/genética , Fenantrenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Western Blotting , Células Cultivadas , Subunidade alfa 2 de Fator de Ligação ao Core/efeitos dos fármacos , Compostos de Epóxi/farmacologia , Humanos , Janus Quinases/efeitos dos fármacos , Janus Quinases/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas de Fusão Oncogênica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/biossíntese , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteína 1 Parceira de Translocação de RUNX1 , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição STAT/efeitos dos fármacos , Fatores de Transcrição STAT/metabolismo
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