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1.
Commun Biol ; 4(1): 1273, 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34754068

RESUMO

Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and oncology drug target that regulates gene transcription through binding to acetylated chromatin via bromodomains. Phosphorylation by casein kinase II (CK2) regulates BRD4 function, is necessary for active transcription and is involved in resistance to BRD4 drug inhibition in triple-negative breast cancer. Here, we provide the first biophysical analysis of BRD4 phospho-regulation. Using integrative structural biology, we show that phosphorylation by CK2 modulates the dimerization of human BRD4. We identify two conserved regions, a coiled-coil motif and the Basic-residue enriched Interaction Domain (BID), essential for the BRD4 structural rearrangement, which we term the phosphorylation-dependent dimerization domain (PDD). Finally, we demonstrate that bivalent inhibitors induce a conformational change within BRD4 dimers in vitro and in cancer cells. Our results enable the proposal of a model for BRD4 activation critical for the characterization of its protein-protein interaction network and for the development of more specific therapeutics.

2.
Nature ; 593(7860): 597-601, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33902106

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex3,4. The m6A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m6A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.

4.
Mol Metab ; 38: 100942, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32217072

RESUMO

BACKGROUND: Virtually all eukaryotic cells contain spatially distinct genomes, a single nuclear genome that harbours the vast majority of genes and much smaller genomes found in mitochondria present at thousands of copies per cell. To generate a coordinated gene response to various environmental cues, the genomes must communicate with each another. Much of this bi-directional crosstalk relies on epigenetic processes, including DNA, RNA, and histone modification pathways. Crucially, these pathways, in turn depend on many metabolites generated in specific pools throughout the cell, including the mitochondria. They also involve the transport of metabolites as well as the enzymes that catalyse these modifications between nuclear and mitochondrial genomes. SCOPE OF REVIEW: This study examines some of the molecular mechanisms by which metabolites influence the activity of epigenetic enzymes, ultimately affecting gene regulation in response to metabolic cues. We particularly focus on the subcellular localisation of metabolite pools and the crosstalk between mitochondrial and nuclear proteins and RNAs. We consider aspects of mitochondrial-nuclear communication involving histone proteins, and potentially their epigenetic marks, and discuss how nuclear-encoded enzymes regulate mitochondrial function through epitranscriptomic pathways involving various classes of RNA molecules within mitochondria. MAJOR CONCLUSIONS: Epigenetic communication between nuclear and mitochondrial genomes occurs at multiple levels, ultimately ensuring a coordinated gene expression response between different genetic environments. Metabolic changes stimulated, for example, by environmental factors, such as diet or physical activity, alter the relative abundances of various metabolites, thereby directly affecting the epigenetic machinery. These pathways, coupled to regulated protein and RNA transport mechanisms, underpin the coordinated gene expression response. Their overall importance to the fitness of a cell is highlighted by the identification of many mutations in the pathways we discuss that have been linked to human disease including cancer.


Assuntos
Comunicação Celular/genética , Núcleo Celular/metabolismo , Mitocôndrias/metabolismo , Animais , Comunicação Celular/fisiologia , Núcleo Celular/genética , Cromatina/metabolismo , Metilação de DNA , Epigênese Genética , Epigenômica/métodos , Genoma Mitocondrial/genética , Genoma Mitocondrial/fisiologia , Histona Acetiltransferases/metabolismo , Histonas/genética , Humanos , Mitocôndrias/genética , RNA/metabolismo
5.
Nat Rev Mol Cell Biol ; 20(10): 573-589, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31270442

RESUMO

Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.


Assuntos
Metilação de DNA , DNA de Neoplasias/metabolismo , Histonas/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Processamento Pós-Transcricional do RNA , RNA Neoplásico/metabolismo , DNA de Neoplasias/genética , Histonas/genética , Proteínas de Neoplasias/genética , Neoplasias/genética , Neoplasias/patologia , RNA Neoplásico/genética
6.
Mol Cell ; 74(6): 1278-1290.e9, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31031083

RESUMO

7-methylguanosine (m7G) is present at mRNA caps and at defined internal positions within tRNAs and rRNAs. However, its detection within low-abundance mRNAs and microRNAs (miRNAs) has been hampered by a lack of sensitive detection strategies. Here, we adapt a chemical reactivity assay to detect internal m7G in miRNAs. Using this technique (Borohydride Reduction sequencing [BoRed-seq]) alongside RNA immunoprecipitation, we identify m7G within a subset of miRNAs that inhibit cell migration. We show that the METTL1 methyltransferase mediates m7G methylation within miRNAs and that this enzyme regulates cell migration via its catalytic activity. Using refined mass spectrometry methods, we map m7G to a single guanosine within the let-7e-5p miRNA. We show that METTL1-mediated methylation augments let-7 miRNA processing by disrupting an inhibitory secondary structure within the primary miRNA transcript (pri-miRNA). These results identify METTL1-dependent N7-methylation of guanosine as a new RNA modification pathway that regulates miRNA structure, biogenesis, and cell migration.


Assuntos
Guanosina/análogos & derivados , Metiltransferases/genética , MicroRNAs/genética , Processamento Pós-Transcricional do RNA , Células A549 , Sequência de Bases , Bioensaio , Células CACO-2 , Movimento Celular , Proliferação de Células , Guanosina/metabolismo , Células HEK293 , Humanos , Metilação , Metiltransferases/metabolismo , MicroRNAs/metabolismo , Conformação de Ácido Nucleico
7.
Epigenetics Chromatin ; 12(1): 21, 2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940194

RESUMO

BACKGROUND: Stem cell differentiation involves major chromatin reorganisation, heterochromatin formation and genomic relocalisation of structural proteins, including heterochromatin protein 1 gamma (HP1γ). As the principal reader of the repressive histone marks H3K9me2/3, HP1 plays a key role in numerous processes including heterochromatin formation and maintenance. RESULTS: We find that HP1γ is citrullinated in mouse embryonic stem cells (mESCs) and this diminishes when cells differentiate, indicating that it is a dynamically regulated post-translational modification during stem cell differentiation. Peptidylarginine deiminase 4, a known regulator of pluripotency, citrullinates HP1γ in vitro. This requires R38 and R39 within the HP1γ chromodomain, and the catalytic activity is enhanced by trimethylated H3K9 (H3K9me3) peptides. Mutation of R38 and R39, designed to mimic citrullination, affects HP1γ binding to H3K9me3-containing peptides. Using live-cell single-particle tracking, we demonstrate that R38 and R39 are important for HP1γ binding to chromatin in vivo. Furthermore, their mutation reduces the residence time of HP1γ on chromatin in differentiating mESCs. CONCLUSION: Citrullination is a novel post-translational modification of the structural heterochromatin protein HP1γ in mESCs that is dynamically regulated during mESC differentiation. The citrullinated residues lie within the HP1γ chromodomain and are important for H3K9me3 binding in vitro and chromatin association in vivo.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Citrulinação , Heterocromatina/metabolismo , Animais , Sítios de Ligação , Diferenciação Celular , Linhagem Celular , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , Heterocromatina/química , Heterocromatina/genética , Código das Histonas , Histonas/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Mutação , Ligação Proteica , Desiminases de Arginina em Proteínas/metabolismo
8.
Nat Commun ; 9(1): 5378, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30568163

RESUMO

We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia (AML). Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4 and MED24. We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.


Assuntos
Leucemia Mieloide Aguda/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular , Diferenciação Celular , Cromatina/metabolismo , Epigênese Genética , Células HL-60 , Hematopoese , Humanos , Células K562 , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Splicing de RNA
9.
Nature ; 552(7683): 126-131, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29186125

RESUMO

N6-methyladenosine (m6A) is an abundant internal RNA modification in both coding and non-coding RNAs that is catalysed by the METTL3-METTL14 methyltransferase complex. However, the specific role of these enzymes in cancer is still largely unknown. Here we define a pathway that is specific for METTL3 and is implicated in the maintenance of a leukaemic state. We identify METTL3 as an essential gene for growth of acute myeloid leukaemia cells in two distinct genetic screens. Downregulation of METTL3 results in cell cycle arrest, differentiation of leukaemic cells and failure to establish leukaemia in immunodeficient mice. We show that METTL3, independently of METTL14, associates with chromatin and localizes to the transcriptional start sites of active genes. The vast majority of these genes have the CAATT-box binding protein CEBPZ present at the transcriptional start site, and this is required for recruitment of METTL3 to chromatin. Promoter-bound METTL3 induces m6A modification within the coding region of the associated mRNA transcript, and enhances its translation by relieving ribosome stalling. We show that genes regulated by METTL3 in this way are necessary for acute myeloid leukaemia. Together, these data define METTL3 as a regulator of a chromatin-based pathway that is necessary for maintenance of the leukaemic state and identify this enzyme as a potential therapeutic target for acute myeloid leukaemia.


Assuntos
Adenosina/análogos & derivados , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Metiltransferases/metabolismo , Regiões Promotoras Genéticas/genética , Biossíntese de Proteínas , Adenosina/genética , Adenosina/metabolismo , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Proliferação de Células/genética , Cromatina/genética , Cromatina/metabolismo , Feminino , Genes Neoplásicos/genética , Humanos , Leucemia Mieloide Aguda/patologia , Metiltransferases/química , Metiltransferases/deficiência , Metiltransferases/genética , Camundongos , Biossíntese de Proteínas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribossomos/metabolismo , Sítio de Iniciação de Transcrição
10.
Angew Chem Int Ed Engl ; 55(38): 11382-6, 2016 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-27530368

RESUMO

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

11.
Artigo em Inglês | MEDLINE | ID: mdl-27446239

RESUMO

Epigenetic inheritance plays a crucial role in many biological processes, such as gene expression in early embryo development, imprinting and the silencing of transposons. It has recently been established that epigenetic effects can be inherited from one generation to the next. Here, we review examples of epigenetic mechanisms governing animal phenotype and behaviour, and we discuss the importance of these findings in respect to animal studies, and livestock in general. Epigenetic parameters orchestrating transgenerational effects, as well as heritable disorders, and the often-overlooked areas of livestock immunity and stress, are also discussed. We highlight the importance of nutrition and how it is linked to epigenetic alteration. Finally, we describe how our understanding of epigenetics is underpinning the latest cancer research and how this can be translated into directed efforts to improve animal health and welfare.

12.
Nat Struct Mol Biol ; 23(7): 673-81, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27294782

RESUMO

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.


Assuntos
Regulação Leucêmica da Expressão Gênica , Histonas/genética , Leucemia Aguda Bifenotípica/genética , Metiltransferases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Acetilação , Animais , Linfócitos B/metabolismo , Linfócitos B/patologia , Proteínas de Ciclo Celular , Proliferação de Células , Cromatina/química , Cromatina/metabolismo , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Feminino , Histona-Lisina N-Metiltransferase , Histonas/metabolismo , Humanos , Leucemia Aguda Bifenotípica/metabolismo , Leucemia Aguda Bifenotípica/patologia , Masculino , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Cultura Primária de Células , Ligação Proteica , Proteômica/métodos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/patologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Transcrição Genética
13.
J Med Chem ; 59(4): 1425-39, 2016 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-25856009

RESUMO

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.


Assuntos
Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Fatores de Transcrição/química
15.
Elife ; 3: e01632, 2014 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-24668167

RESUMO

Post-translational modifications of proteins have emerged as a major mechanism for regulating gene expression. However, our understanding of how histone modifications directly affect chromatin function remains limited. In this study, we investigate acetylation of histone H3 at lysine 64 (H3K64ac), a previously uncharacterized acetylation on the lateral surface of the histone octamer. We show that H3K64ac regulates nucleosome stability and facilitates nucleosome eviction and hence gene expression in vivo. In line with this, we demonstrate that H3K64ac is enriched in vivo at the transcriptional start sites of active genes and it defines transcriptionally active chromatin. Moreover, we find that the p300 co-activator acetylates H3K64, and consistent with a transcriptional activation function, H3K64ac opposes its repressive counterpart H3K64me3. Our findings reveal an important role for a histone modification within the nucleosome core as a regulator of chromatin function and they demonstrate that lateral surface modifications can define functionally opposing chromatin states. DOI: http://dx.doi.org/10.7554/eLife.01632.001.


Assuntos
Montagem e Desmontagem da Cromatina , Histonas/metabolismo , Nucleossomos/metabolismo , Processamento de Proteína Pós-Traducional , Transcrição Genética , Ativação Transcricional , Acetilação , Animais , Células-Tronco Embrionárias/metabolismo , Histonas/química , Humanos , Cinética , Lisina , Masculino , Metilação , Camundongos , Células NIH 3T3 , Células-Tronco Neurais/metabolismo , Conformação de Ácido Nucleico , Conformação Proteica , Estabilidade Proteica , Transfecção , Proteínas de Xenopus/química , Proteínas de Xenopus/metabolismo , Xenopus laevis , Fatores de Transcrição de p300-CBP/metabolismo
17.
Cell Rep ; 2(3): 470-7, 2012 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-22999934

RESUMO

The JAK2 tyrosine kinase is a critical mediator of cytokine-induced signaling. It plays a role in the nucleus, where it regulates transcription by phosphorylating histone H3 at tyrosine 41 (H3Y41ph). We used chromatin immunoprecipitation coupled to massively parallel DNA sequencing (ChIP-seq) to define the genome-wide pattern of H3Y41ph in human erythroid leukemia cells. Our results indicate that H3Y41ph is located at three distinct sites: (1) at a subset of active promoters, where it overlaps with H3K4me3, (2) at distal cis-regulatory elements, where it coincides with the binding of STAT5, and (3) throughout the transcribed regions of active, tissue-specific hematopoietic genes. Together, these data extend our understanding of this conserved and essential signaling pathway and provide insight into the mechanisms by which extracellular stimuli may lead to the coordinated regulation of transcription.


Assuntos
Histonas/metabolismo , Janus Quinase 2/metabolismo , Regiões Promotoras Genéticas/fisiologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/fisiologia , Transcrição Genética/fisiologia , Linhagem Celular Tumoral , Histonas/genética , Humanos , Janus Quinase 2/genética , Fosforilação/fisiologia , Fator de Transcrição STAT5/genética
19.
Cell Res ; 21(3): 381-95, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21321607

RESUMO

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.


Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Heterocromatina/química , Histona Desmetilases/metabolismo , Processamento de Proteína Pós-Traducional
20.
PLoS One ; 6(1): e16330, 2011 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-21297973

RESUMO

Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation that were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors including Gata2, Gfi1 and Sfpi1/Pu.1. In particular, downregulation of Gata2 expression was mirrored by abundant GATA motifs in regions of reduced histone acetylation suggesting an important role in leukaemogenic transcriptional reprogramming. Forced re-expression of Gata2 was not compatible with sustained growth of leukaemic cells thus suggesting a previously unrecognised role for Gata2 in downregulation during the development of AML. Additionally, large scale human AML datasets revealed significantly higher expression of GATA2 in CD34+ cells from healthy controls compared with AML blast cells. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer.


Assuntos
Fator de Transcrição GATA2/genética , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/genética , Transcrição Genética , Acetilação , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Leucemia Mieloide Aguda/patologia , Camundongos , Células-Tronco Neoplásicas , Análise de Sequência de DNA , Fatores de Transcrição/genética
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