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1.
Cell ; 185(1): 204-217.e14, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34965378

RESUMO

Conifers dominate the world's forest ecosystems and are the most widely planted tree species. Their giant and complex genomes present great challenges for assembling a complete reference genome for evolutionary and genomic studies. We present a 25.4-Gb chromosome-level assembly of Chinese pine (Pinus tabuliformis) and revealed that its genome size is mostly attributable to huge intergenic regions and long introns with high transposable element (TE) content. Large genes with long introns exhibited higher expressions levels. Despite a lack of recent whole-genome duplication, 91.2% of genes were duplicated through dispersed duplication, and expanded gene families are mainly related to stress responses, which may underpin conifers' adaptation, particularly in cold and/or arid conditions. The reproductive regulation network is distinct compared with angiosperms. Slow removal of TEs with high-level methylation may have contributed to genomic expansion. This study provides insights into conifer evolution and resources for advancing research on conifer adaptation and development.


Assuntos
Epigenoma , Evolução Molecular , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Pinus/genética , Aclimatação/genética , Cromossomos de Plantas/genética , Cycadopsida/genética , Elementos de DNA Transponíveis/genética , Florestas , Redes Reguladoras de Genes , Tamanho do Genoma , Genômica/métodos , Íntrons , Magnoliopsida/genética
2.
Cell ; 181(5): 997-1003.e9, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32359424

RESUMO

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2 infection and was first reported in central China in December 2019. Extensive molecular surveillance in Guangdong, China's most populous province, during early 2020 resulted in 1,388 reported RNA-positive cases from 1.6 million tests. In order to understand the molecular epidemiology and genetic diversity of SARS-CoV-2 in China, we generated 53 genomes from infected individuals in Guangdong using a combination of metagenomic sequencing and tiling amplicon approaches. Combined epidemiological and phylogenetic analyses indicate multiple independent introductions to Guangdong, although phylogenetic clustering is uncertain because of low virus genetic variation early in the pandemic. Our results illustrate how the timing, size, and duration of putative local transmission chains were constrained by national travel restrictions and by the province's large-scale intensive surveillance and intervention measures. Despite these successes, COVID-19 surveillance in Guangdong is still required, because the number of cases imported from other countries has increased.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Teorema de Bayes , COVID-19 , China/epidemiologia , Infecções por Coronavirus/virologia , Monitoramento Epidemiológico , Humanos , Funções Verossimilhança , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2 , Viagem
3.
Cell ; 182(5): 1328-1340.e13, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32814014

RESUMO

Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.


Assuntos
Variação Genética/genética , Doenças Transmitidas por Carrapatos/microbiologia , Carrapatos/genética , Animais , Linhagem Celular , Vetores de Doenças , Especificidade de Hospedeiro/genética
4.
Cell ; 177(4): 1035-1049.e19, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31031003

RESUMO

We performed the first proteogenomic study on a prospectively collected colon cancer cohort. Comparative proteomic and phosphoproteomic analysis of paired tumor and normal adjacent tissues produced a catalog of colon cancer-associated proteins and phosphosites, including known and putative new biomarkers, drug targets, and cancer/testis antigens. Proteogenomic integration not only prioritized genomically inferred targets, such as copy-number drivers and mutation-derived neoantigens, but also yielded novel findings. Phosphoproteomics data associated Rb phosphorylation with increased proliferation and decreased apoptosis in colon cancer, which explains why this classical tumor suppressor is amplified in colon tumors and suggests a rationale for targeting Rb phosphorylation in colon cancer. Proteomics identified an association between decreased CD8 T cell infiltration and increased glycolysis in microsatellite instability-high (MSI-H) tumors, suggesting glycolysis as a potential target to overcome the resistance of MSI-H tumors to immune checkpoint blockade. Proteogenomics presents new avenues for biological discoveries and therapeutic development.


Assuntos
Neoplasias do Colo/genética , Neoplasias do Colo/terapia , Proteogenômica/métodos , Apoptose/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos , Proliferação de Células/genética , Neoplasias do Colo/metabolismo , Genômica/métodos , Glicólise , Humanos , Instabilidade de Microssatélites , Mutação , Fosforilação , Estudos Prospectivos , Proteômica/métodos , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo
5.
Mol Cell ; 84(7): 1206-1223.e15, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38423014

RESUMO

Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70-KU80, LIG4, XRCC4, and XLF, is central to non-homologous end joining (NHEJ) repair of chromatinized DNA double-strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells. Mechanistically, MiDAC removes combinatorial acetyl marks on histone H2A (H2AK5acK9ac) around DSB-proximal chromatin, suppressing hyperaccumulation of bromodomain-containing protein BRD4 that would otherwise undergo liquid-liquid phase separation with KU80 and prevent the proper installation of LIG4-XRCC4-XLF onto DSB ends. This study provides mechanistic insight into the control of NHEJ synaptic complex assembly by a specific chromatin signature and highlights the critical role of H2A hypoacetylation in restraining unscheduled compartmentalization of DNA repair machinery.


Assuntos
Cromatina , Proteínas Nucleares , Animais , Cromatina/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , DNA/genética , Reparo do DNA por Junção de Extremidades , Histonas/genética , Histonas/metabolismo , Pareamento Cromossômico , Autoantígeno Ku/genética , Autoantígeno Ku/metabolismo , Mamíferos/metabolismo
6.
Cell ; 166(3): 755-765, 2016 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-27372738

RESUMO

To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.


Assuntos
Proteínas de Neoplasias/genética , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Ovarianas/genética , Proteoma , Acetilação , Instabilidade Cromossômica , Reparo do DNA , DNA de Neoplasias , Feminino , Dosagem de Genes , Humanos , Espectrometria de Massas , Fosfoproteínas/genética , Processamento de Proteína Pós-Traducional , Análise de Sobrevida
7.
Mol Cell ; 83(2): 281-297.e10, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36586411

RESUMO

As a key component of the inflammasome, NLRP3 is a critical intracellular danger sensor emerging as an important clinical target in inflammatory diseases. However, little is known about the mechanisms that determine the kinetics of NLRP3 inflammasome stability and activity to ensure effective and controllable inflammatory responses. Here, we show that S-palmitoylation acts as a brake to turn NLRP3 inflammasome off. zDHHC12 is identified as the S-acyltransferase for NLRP3 palmitoylation, which promotes its degradation through the chaperone-mediated autophagy pathway. Zdhhc12 deficiency in mice enhances inflammatory symptoms and lethality following alum-induced peritonitis and LPS-induced endotoxic shock. Notably, several disease-associated mutations in NLRP3 are associated with defective palmitoylation, resulting in overt NLRP3 inflammasome activation. Thus, our findings identify zDHHC12 as a repressor of NLRP3 inflammasome activation and uncover a previously unknown regulatory mechanism by which the inflammasome pathway is tightly controlled by the dynamic palmitoylation of NLRP3.


Assuntos
Autofagia Mediada por Chaperonas , Inflamassomos , Animais , Camundongos , Aciltransferases , Autofagia , Inflamassomos/metabolismo , Inflamação/induzido quimicamente , Inflamação/genética , Lipoilação , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
8.
Mol Cell ; 81(22): 4747-4756.e7, 2021 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-34648747

RESUMO

The CRISPR-Cas12a system shows unique features compared with widely used Cas9, making it an attractive and potentially more precise alternative. However, the adoption of this system has been hindered by its relatively low editing efficiency. Guided by physical chemical principles, we covalently conjugated 5' terminal modified CRISPR RNA (crRNA) to a site-specifically modified Cas12a through biorthogonal chemical reaction. The genome editing efficiency of the resulting conjugated Cas12a complex (cCas12a) was substantially higher than that of the wild-type complex. We also demonstrated that cCas12a could be used for precise gene knockin and multiplex gene editing in a chimeric antigen receptor T cell preparation with efficiency much higher than that of the wild-type system. Overall, our findings indicate that covalently linking Cas nuclease and crRNA is an effective approach to improve the Cas12a-based genome editing system and could potentially provide an insight into engineering other Cas family members with low efficiency as well.


Assuntos
Proteínas de Bactérias/genética , Proteínas Associadas a CRISPR/genética , Sistemas CRISPR-Cas , Endodesoxirribonucleases/genética , Edição de Genes , Receptores de Antígenos Quiméricos/metabolismo , Acidaminococcus , Animais , DNA/química , DNA/metabolismo , Endonucleases/metabolismo , Escherichia coli/metabolismo , Técnicas de Introdução de Genes , Técnicas Genéticas , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Técnicas In Vitro , Células K562 , Camundongos , Mutagênese , RNA/metabolismo , Espectrometria de Massas em Tandem
9.
Cell ; 155(6): 1380-95, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24315104

RESUMO

Transcription factor activity and turnover are functionally linked, but the global patterns by which DNA-bound regulators are eliminated remain poorly understood. We established an assay to define the chromosomal location of DNA-associated proteins that are slated for degradation by the ubiquitin-proteasome system. The genome-wide map described here ties proteolysis in mammalian cells to active enhancers and to promoters of specific gene families. Nuclear-encoded mitochondrial genes in particular correlate with protein elimination, which positively affects their transcription. We show that the nuclear receptor corepressor NCoR1 is a key target of proteolysis and physically interacts with the transcription factor CREB. Proteasome inhibition stabilizes NCoR1 in a site-specific manner and restrains mitochondrial activity by repressing CREB-sensitive genes. In conclusion, this functional map of nuclear proteolysis links chromatin architecture with local protein stability and identifies proteolytic derepression as highly dynamic in regulating the transcription of genes involved in energy metabolism.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação da Expressão Gênica , Correpressor 1 de Receptor Nuclear/metabolismo , Proteólise , Elementos Reguladores de Transcrição , Animais , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Mitocôndrias/metabolismo , Ubiquitinação
10.
Nature ; 612(7941): 673-678, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36450987

RESUMO

Electrochemical saline water electrolysis using renewable energy as input is a highly desirable and sustainable method for the mass production of green hydrogen1-7; however, its practical viability is seriously challenged by insufficient durability because of the electrode side reactions and corrosion issues arising from the complex components of seawater. Although catalyst engineering using polyanion coatings to suppress corrosion by chloride ions or creating highly selective electrocatalysts has been extensively exploited with modest success, it is still far from satisfactory for practical applications8-14. Indirect seawater splitting by using a pre-desalination process can avoid side-reaction and corrosion problems15-21, but it requires additional energy input, making it economically less attractive. In addition, the independent bulky desalination system makes seawater electrolysis systems less flexible in terms of size. Here we propose a direct seawater electrolysis method for hydrogen production that radically addresses the side-reaction and corrosion problems. A demonstration system was stably operated at a current density of 250 milliamperes per square centimetre for over 3,200 hours under practical application conditions without failure. This strategy realizes efficient, size-flexible and scalable direct seawater electrolysis in a way similar to freshwater splitting without a notable increase in operation cost, and has high potential for practical application. Importantly, this configuration and mechanism promises further applications in simultaneous water-based effluent treatment and resource recovery and hydrogen generation in one step.

11.
Annu Rev Pharmacol Toxicol ; 64: 455-479, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-37738504

RESUMO

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.


Assuntos
Medicina de Precisão , Proteogenômica , Humanos , Proteômica , Genômica , Espectrometria de Massas
12.
Proc Natl Acad Sci U S A ; 121(29): e2320709121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38985760

RESUMO

The Type-I interferon (IFN-I) response is the major outcome of stimulator of interferon genes (STING) activation in innate cells. STING is more abundantly expressed in adaptive T cells; nevertheless, its intrinsic function in T cells remains unclear. Intriguingly, we previously demonstrated that STING activation in T cells activates widespread IFN-independent activities, which stands in contrast to the well-known STING-mediated IFN response. Here, we have identified that STING activation induces regulatory T cells (Tregs) differentiation independently of IRF3 and IFN. Specifically, the translocation of STING from the endoplasmic reticulum to the Golgi activates mitogen-activated protein kinase (MAPK) activity, which subsequently triggers transcription factor cAMP response element-binding protein (CREB) activation. The activation of the STING-MAPK-CREB signaling pathway induces the expression of many cytokine genes, including interleukin-2 (IL-2) and transforming growth factor-beta 2 (TGF-ß2), to promote the Treg differentiation. Genetic knockdown of MAPK p38 or pharmacological inhibition of MAPK p38 or CREB markedly inhibits STING-mediated Treg differentiation. Administration of the STING agonist also promotes Treg differentiation in mice. In the Trex1-/- autoimmune disease mouse model, we demonstrate that intrinsic STING activation in CD4+ T cells can drive Treg differentiation, potentially counterbalancing the autoimmunity associated with Trex1 deficiency. Thus, STING-MAPK-CREB represents an IFN-independent signaling axis of STING that may have profound effects on T cell effector function and adaptive immunity.


Assuntos
Diferenciação Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Proteínas de Membrana , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Camundongos , Transdução de Sinais , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Transporte Proteico , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 3 de Interferon/genética , Camundongos Knockout , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Proc Natl Acad Sci U S A ; 121(25): e2316615121, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38861602

RESUMO

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.


Assuntos
Antineoplásicos , Irídio , Metano , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Irídio/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metano/análogos & derivados , Metano/química , Metano/farmacologia , Proteínas dos Microfilamentos/metabolismo , Metástase Neoplásica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Masculino
14.
Blood ; 143(26): 2749-2762, 2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-38498025

RESUMO

ABSTRACT: Identifying and targeting microenvironment-driven pathways that are active across acute myeloid leukemia (AML) genetic subtypes should allow the development of more broadly effective therapies. The proinflammatory cytokine interleukin-1ß (IL-1ß) is abundant in the AML microenvironment and promotes leukemic growth. Through RNA-sequencing analysis, we identify that IL-1ß-upregulated ASF1B (antisilencing function-1B), a histone chaperone, in AML progenitors compared with healthy progenitors. ASF1B, along with its paralogous protein ASF1A, recruits H3-H4 histones onto the replication fork during S-phase, a process regulated by Tousled-like kinase 1 and 2 (TLKs). Although ASF1s and TLKs are known to be overexpressed in multiple solid tumors and associated with poor prognosis, their functional roles in hematopoiesis and inflammation-driven leukemia remain unexplored. In this study, we identify that ASF1s and TLKs are overexpressed in multiple genetic subtypes of AML. We demonstrate that depletion of ASF1s significantly reduces leukemic cell growth in both in vitro and in vivo models using human cells. Using a murine model, we show that overexpression of ASF1B accelerates leukemia progression. Moreover, Asf1b or Tlk2 deletion delayed leukemia progression, whereas these proteins are dispensable for normal hematopoiesis. Through proteomics and phosphoproteomics analyses, we uncover that the TLK-ASF1 pathway promotes leukemogenesis by affecting the cell cycle and DNA damage pathways. Collectively, our findings identify the TLK1-ASF1 pathway as a novel mediator of inflammatory signaling and a promising therapeutic target for AML treatment across diverse genetic subtypes. Selective inhibition of this pathway offers potential opportunities to intervene effectively, address intratumoral heterogeneity, and ultimately improve clinical outcomes in AML.


Assuntos
Proteínas de Ciclo Celular , Progressão da Doença , Interleucina-1beta , Leucemia Mieloide Aguda , Proteínas Serina-Treonina Quinases , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Humanos , Animais , Camundongos , Interleucina-1beta/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Chaperonas de Histonas/metabolismo , Chaperonas de Histonas/genética , Histonas/metabolismo , Histonas/genética , Linhagem Celular Tumoral , Fatores de Processamento de Serina-Arginina/metabolismo , Fatores de Processamento de Serina-Arginina/genética
15.
Blood ; 144(1): 84-98, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38579286

RESUMO

ABSTRACT: The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because of the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role in LSCs and AML pathogenesis is unknown. Here, we define GADD45A as a key downstream target of G protein-coupled receptor (LGR)4 pathway and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo, and reduces levels of reactive oxygen species (ROS), accompanied by a decreased response to ROS-associated genotoxic agents (eg, ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype on serial transplantation in mice. Our single-cell cellular indexing of transcriptomes and epitopes by sequencing analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification, such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in patients with AML. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.


Assuntos
Proteínas de Ciclo Celular , Ferroptose , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Animais , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , Camundongos , Humanos , Ferroptose/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Camundongos Knockout , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas GADD45
16.
Nat Chem Biol ; 20(6): 721-731, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38302606

RESUMO

Protein labeling approaches are important to study proteins in living cells, and genome editing tools make it possible to tag endogenous proteins to address the concerns associated with overexpression. Here we established RNA editing-mediated noncanonical amino acids (ncAAs) protein tagging (RENAPT) to site-specifically label endogenous proteins with ncAAs in living cells. RENAPT labels protein in a temporary and nonheritable manner and is not restricted by protospacer adjacent motif sequence. Using a fluorescent ncAA or ncAA with a bio-orthogonal reaction handle for subsequent dye labeling, we demonstrated that a variety of endogenous proteins can be imaged at their specific subcellular locations. In addition, two proteins can be tagged individually and simultaneously using two different ncAAs. Furthermore, endogenous ion channels and neuron-specific proteins can be real-time labeled in primary neurons. Thus, RENAPT presents a promising platform with broad applicability for tagging endogenous proteins in living cells to study their localization and functions.


Assuntos
Código Genético , Edição de RNA , Humanos , Animais , Neurônios/metabolismo , Células HEK293 , Aminoácidos/química , Aminoácidos/metabolismo , Aminoácidos/genética , Proteínas/química , Proteínas/genética , Proteínas/metabolismo , Corantes Fluorescentes/química
17.
Nature ; 579(7798): 224-228, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123353

RESUMO

Large-scale energy storage is becoming increasingly critical to balancing renewable energy production and consumption1. Organic redox flow batteries, made from inexpensive and sustainable redox-active materials, are promising storage technologies that are cheaper and less environmentally hazardous than vanadium-based batteries, but they have shorter lifetimes and lower energy density2,3. Thus, fundamental insight at the molecular level is required to improve performance4,5. Here we report two in situ nuclear magnetic resonance (NMR) methods of studying redox flow batteries, which are applied to two redox-active electrolytes: 2,6-dihydroxyanthraquinone (DHAQ) and 4,4'-((9,10-anthraquinone-2,6-diyl)dioxy) dibutyrate (DBEAQ). In the first method, we monitor the changes in the 1H NMR shift of the liquid electrolyte as it flows out of the electrochemical cell. In the second method, we observe the changes that occur simultaneously in the positive and negative electrodes in the full electrochemical cell. Using the bulk magnetization changes (observed via the 1H NMR shift of the water resonance) and the line broadening of the 1H shifts of the quinone resonances as a function of the state of charge, we measure the potential differences of the two single-electron couples, identify and quantify the rate of electron transfer between the reduced and oxidized species, and determine the extent of electron delocalization of the unpaired spins over the radical anions. These NMR techniques enable electrolyte decomposition and battery self-discharge to be explored in real time, and show that DHAQ is decomposed electrochemically via a reaction that can be minimized by limiting the voltage used on charging. We foresee applications of these NMR methods in understanding a wide range of redox processes in flow and other electrochemical systems.


Assuntos
Fontes de Energia Elétrica , Espectroscopia de Ressonância Magnética , Eletrólitos/química , Elétrons , Oxirredução
18.
Hum Mol Genet ; 32(22): 3181-3193, 2023 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-37622920

RESUMO

Prostate cancer (PCa) brings huge public health burden in men. A growing number of conventional observational studies report associations of multiple circulating proteins with PCa risk. However, the existing findings may be subject to incoherent biases of conventional epidemiologic studies. To better characterize their associations, herein, we evaluated associations of genetically predicted concentrations of plasma proteins with PCa risk. We developed comprehensive genetic prediction models for protein levels in plasma. After testing 1308 proteins in 79 194 cases and 61 112 controls of European ancestry included in the consortia of BPC3, CAPS, CRUK, PEGASUS, and PRACTICAL, 24 proteins showed significant associations with PCa risk, including 16 previously reported proteins and eight novel proteins. Of them, 14 proteins showed negative associations and 10 showed positive associations with PCa risk. For 18 of the identified proteins, potential functional somatic changes of encoding genes were detected in PCa patients in The Cancer Genome Atlas (TCGA). Genes encoding these proteins were significantly involved in cancer-related pathways. We further identified drugs targeting the identified proteins, which may serve as candidates for drug repurposing for treating PCa. In conclusion, this study identifies novel protein biomarker candidates for PCa risk, which may provide new perspectives on the etiology of PCa and improve its therapeutic strategies.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Proteínas Sanguíneas/genética , Biomarcadores Tumorais/genética
19.
EMBO J ; 40(4): e104729, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33349972

RESUMO

The regulatory circuitry underlying embryonic stem (ES) cell self-renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA-binding proteins (RBPs) have essential roles in RNA-mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified seven RBPs played important roles for the exit from pluripotency of ES cells. We characterized hnRNPLL, which mainly functions as a global regulator of alternative splicing in ES cells. Specifically, hnRNPLL promotes multiple ES cell-preferred exon skipping events during the onset of ES cell differentiation. hnRNPLL depletion thus leads to sustained expression of ES cell-preferred isoforms, resulting in a differentiation deficiency that causes developmental defects and growth impairment in hnRNPLL-KO mice. In particular, hnRNPLL-mediated alternative splicing of two transcription factors, Bptf and Tbx3, is important for pluripotency exit. These data uncover the critical role of RBPs in pluripotency exit and suggest the application of targeting RBPs in controlling ES cell fate.


Assuntos
Processamento Alternativo , Antígenos Nucleares/metabolismo , Diferenciação Celular , Células-Tronco Embrionárias/citologia , Ribonucleoproteínas Nucleares Heterogêneas/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Pluripotentes/citologia , Proteínas com Domínio T/metabolismo , Fatores de Transcrição/metabolismo , Animais , Antígenos Nucleares/genética , Células-Tronco Embrionárias/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Células-Tronco Pluripotentes/metabolismo , Isoformas de Proteínas , Proteínas com Domínio T/genética , Fatores de Transcrição/genética
20.
Brief Bioinform ; 25(1)2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-38171932

RESUMO

N6-methyladenosine (m6A) RNA methylation is the predominant epigenetic modification for mRNAs that regulates various cancer-related pathways. However, the prognostic significance of m6A modification regulators remains unclear in glioma. By integrating the TCGA lower-grade glioma (LGG) and glioblastoma multiforme (GBM) gene expression data, we demonstrated that both the m6A regulators and m6A-target genes were associated with glioma prognosis and activated various cancer-related pathways. Then, we paired m6A regulators and their target genes as m6A-related gene pairs (MGPs) using the iPAGE algorithm, among which 122 MGPs were significantly reversed in expression between LGG and GBM. Subsequently, we employed LASSO Cox regression analysis to construct an MGP signature (MrGPS) to evaluate glioma prognosis. MrGPS was independently validated in CGGA and GEO glioma cohorts with high accuracy in predicting overall survival. The average area under the receiver operating characteristic curve (AUC) at 1-, 3- and 5-year intervals were 0.752, 0.853 and 0.831, respectively. Combining clinical factors of age and radiotherapy, the AUC of MrGPS was much improved to around 0.90. Furthermore, CIBERSORT and TIDE algorithms revealed that MrGPS is indicative for the immune infiltration level and the response to immune checkpoint inhibitor therapy in glioma patients. In conclusion, our study demonstrated that m6A methylation is a prognostic factor for glioma and the developed prognostic model MrGPS holds potential as a valuable tool for enhancing patient management and facilitating accurate prognosis assessment in cases of glioma.


Assuntos
Glioblastoma , Glioma , Humanos , Glioma/genética , Adenina , Adenosina/genética
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