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1.
Mol Cell ; 84(12): 2238-2254.e11, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38870936

RESUMEN

Transcriptional coregulators and transcription factors (TFs) contain intrinsically disordered regions (IDRs) that are critical for their association and function in gene regulation. More recently, IDRs have been shown to promote multivalent protein-protein interactions between coregulators and TFs to drive their association into condensates. By contrast, here we demonstrate how the IDR of the corepressor LSD1 excludes TF association, acting as a dynamic conformational switch that tunes repression of active cis-regulatory elements. Hydrogen-deuterium exchange shows that the LSD1 IDR interconverts between transient open and closed conformational states, the latter of which inhibits partitioning of the protein's structured domains with TF condensates. This autoinhibitory switch controls leukemic differentiation by modulating repression of active cis-regulatory elements bound by LSD1 and master hematopoietic TFs. Together, these studies unveil alternative mechanisms by which disordered regions and their dynamic crosstalk with structured regions can shape coregulator-TF interactions to control cis-regulatory landscapes and cell fate.


Asunto(s)
Elementos de Facilitación Genéticos , Histona Demetilasas , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Humanos , Proteínas Intrínsecamente Desordenadas/metabolismo , Proteínas Intrínsecamente Desordenadas/genética , Proteínas Intrínsecamente Desordenadas/química , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Animales , Unión Proteica , Ratones , Diferenciación Celular , Silenciador del Gen
2.
Mol Cell ; 82(20): 3794-3809.e8, 2022 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-36206766

RESUMEN

Neuronal activity induces topoisomerase IIß (Top2B) to generate DNA double-strand breaks (DSBs) within the promoters of neuronal early response genes (ERGs) and facilitate their transcription, and yet, the mechanisms that control Top2B-mediated DSB formation are unknown. Here, we report that stimulus-dependent calcium influx through NMDA receptors activates the phosphatase calcineurin to dephosphorylate Top2B at residues S1509 and S1511, which stimulates its DNA cleavage activity and induces it to form DSBs. Exposing mice to a fear conditioning paradigm also triggers Top2B dephosphorylation at S1509 and S1511 in the hippocampus, indicating that calcineurin also regulates Top2B-mediated DSB formation following physiological neuronal activity. Furthermore, calcineurin-Top2B interactions following neuronal activity and sites that incur activity-induced DSBs are preferentially localized at the nuclear periphery in neurons. Together, these results reveal how radial gene positioning and the compartmentalization of activity-dependent signaling govern the position and timing of activity-induced DSBs and regulate gene expression patterns in neurons.


Asunto(s)
Calcineurina , Roturas del ADN de Doble Cadena , ADN-Topoisomerasas de Tipo II , Neuronas , Animales , Ratones , Calcineurina/genética , Calcineurina/metabolismo , Calcio/metabolismo , ADN , ADN-Topoisomerasas de Tipo II/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/genética
3.
Nat Cell Biol ; 26(7): 1165-1175, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38926506

RESUMEN

KMT2C and KMT2D, encoding histone H3 lysine 4 methyltransferases, are among the most commonly mutated genes in triple-negative breast cancer (TNBC). However, how these mutations may shape epigenomic and transcriptomic landscapes to promote tumorigenesis is largely unknown. Here we describe that deletion of Kmt2c or Kmt2d in non-metastatic murine models of TNBC drives metastasis, especially to the brain. Global chromatin profiling and chromatin immunoprecipitation followed by sequencing revealed altered H3K4me1, H3K27ac and H3K27me3 chromatin marks in knockout cells and demonstrated enhanced binding of the H3K27me3 lysine demethylase KDM6A, which significantly correlated with gene expression. We identified Mmp3 as being commonly upregulated via epigenetic mechanisms in both knockout models. Consistent with these findings, samples from patients with KMT2C-mutant TNBC have higher MMP3 levels. Downregulation or pharmacological inhibition of KDM6A diminished Mmp3 upregulation induced by the loss of histone-lysine N-methyltransferase 2 (KMT2) and prevented brain metastasis similar to direct downregulation of Mmp3. Taken together, we identified the KDM6A-matrix metalloproteinase 3 axis as a key mediator of KMT2C/D loss-driven metastasis in TNBC.


Asunto(s)
Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Histona Demetilasas , Metaloproteinasa 3 de la Matriz , Neoplasias de la Mama Triple Negativas , Regulación hacia Arriba , Animales , Humanos , Metaloproteinasa 3 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Histona Demetilasas/metabolismo , Histona Demetilasas/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/metabolismo , Femenino , Línea Celular Tumoral , Ratones , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ratones Noqueados , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Epigénesis Genética , Proteína de la Leucemia Mieloide-Linfoide
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