RESUMEN
In this issue of Molecular Cell, Cheng et al. describe an unexpected role for the histone methyltransferases MLL3 and MLL4 in the repression of tissue-specific promoters, a function that prevents precocious cell differentiation in the skeletal muscle lineage.
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Cromatina , Regulación del Desarrollo de la Expresión Génica , Histonas/genética , Desarrollo de Músculos/genética , Mioblastos/metabolismo , Animales , HumanosRESUMEN
Hematopoietic cancers are often initiated by deregulation of the transcriptional machinery. Prominent among such regulators are the sequence-specific DNA-binding transcription factors (TFs), which bind to enhancer and promoter elements in the genome to control gene expression through the recruitment of cofactors. Remarkably, perturbing the function of even a single TF or cofactor can modulate the active enhancer landscape of a cell; conversely, knowledge of the enhancer configuration can be used to discover functionally important TFs in a given cellular process. Our expanding insight into enhancer function can be attributed to the emergence of genome-scale measurements of enhancer activity, which can be applied to virtually any cell type to expose regulatory mechanisms. Such approaches are beginning to reveal the abnormal enhancer configurations present in cancer cells, thereby providing a framework for understanding how transcriptional dysregulation can lead to malignancy. Here, we review the evidence for alterations in enhancer landscapes contributing to the pathogenesis of leukemia, a malignancy in which enhancer-binding proteins and enhancer DNA itself are altered via genetic mutation. We will also highlight examples of small molecules that reprogram the enhancer landscape of leukemia cells in association with therapeutic benefit.
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Elementos de Facilitación Genéticos , Regulación Leucémica de la Expresión Génica , Leucemia , Mutación , Proteínas de Neoplasias , Factores de Transcripción , Animales , Humanos , Leucemia/genética , Leucemia/metabolismo , Leucemia/patología , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.
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Reparación del ADN/genética , Modelos Animales de Enfermedad , Marcación de Gen/métodos , Terapia Genética/métodos , Genoma/genética , Hemofilia B/genética , Hemostasis , Animales , Secuencia de Bases , Línea Celular Tumoral , Roturas del ADN de Doble Cadena , Endonucleasas/química , Endonucleasas/genética , Endonucleasas/metabolismo , Exones/genética , Factor IX/análisis , Factor IX/genética , Vectores Genéticos/genética , Células HEK293 , Hemofilia B/fisiopatología , Humanos , Intrones/genética , Hígado/metabolismo , Regeneración Hepática , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Fenotipo , Homología de Secuencia , Dedos de ZincRESUMEN
The bromodomain and extraterminal (BET) protein BRD4 can physically interact with the Mediator complex, but the relevance of this association to the therapeutic effects of BET inhibitors in cancer is unclear. Here, we show that BET inhibition causes a rapid release of Mediator from a subset of cis-regulatory elements in the genome of acute myeloid leukemia (AML) cells. These sites of Mediator eviction were highly correlated with transcriptional suppression of neighboring genes, which are enriched for targets of the transcription factor MYB and for functions related to leukemogenesis. A shRNA screen of Mediator in AML cells identified the MED12, MED13, MED23, and MED24 subunits as performing a similar regulatory function to BRD4 in this context, including a shared role in sustaining a block in myeloid maturation. These findings suggest that the interaction between BRD4 and Mediator has functional importance for gene-specific transcriptional activation and for AML maintenance.
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Complejo Mediador/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de Transcripción/antagonistas & inhibidores , Animales , Azepinas/farmacología , Crisis Blástica/genética , Crisis Blástica/patología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular Tumoral , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Genoma , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Subunidades de Proteína/metabolismo , ARN Polimerasa II/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacos , Triazoles/farmacologíaRESUMEN
Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery.
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Most mammalian transcription factors (TFs) and cofactors occupy thousands of genomic sites and modulate the expression of large gene networks to implement their biological functions. In this study, we describe an exception to this paradigm. TRIM33 is identified here as a lineage dependency in B cell neoplasms and is shown to perform this essential function by associating with a single cis element. ChIP-seq analysis of TRIM33 in murine B cell leukemia revealed a preferential association with two lineage-specific enhancers that harbor an exceptional density of motifs recognized by the PU.1 TF. TRIM33 is recruited to these elements by PU.1, yet acts to antagonize PU.1 function. One of the PU.1/TRIM33 co-occupied enhancers is upstream of the pro-apoptotic gene Bim, and deleting this enhancer renders TRIM33 dispensable for leukemia cell survival. These findings reveal an essential role for TRIM33 in preventing apoptosis in B lymphoblastic leukemia by interfering with enhancer-mediated Bim activation.