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1.
Genes Dev ; 37(19-20): 883-900, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37890975

RESUMEN

Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before in MECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.


Asunto(s)
Cromatina , Síndrome de Rett , Femenino , Humanos , Masculino , Ratones , Animales , Cromatina/metabolismo , Encéfalo/metabolismo , Proteína 2 de Unión a Metil-CpG/genética , Síndrome de Rett/genética , Mutación , Neuronas/metabolismo
2.
Nat Commun ; 12(1): 5579, 2021 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-34552088

RESUMEN

Expression of a few master transcription factors can reprogram the epigenetic landscape and three-dimensional chromatin topology of differentiated cells and achieve pluripotency. During reprogramming, thousands of long-range chromatin contacts are altered, and changes in promoter association with enhancers dramatically influence transcription. Molecular participants at these sites have been identified, but how this re-organization might be orchestrated is not known. Biomolecular condensation is implicated in subcellular organization, including the recruitment of RNA polymerase in transcriptional activation. Here, we show that reprogramming factor KLF4 undergoes biomolecular condensation even in the absence of its intrinsically disordered region. Liquid-liquid condensation of the isolated KLF4 DNA binding domain with a DNA fragment from the NANOG proximal promoter is enhanced by CpG methylation of a KLF4 cognate binding site. We propose KLF4-mediated condensation as one mechanism for selectively organizing and re-organizing the genome based on the local sequence and epigenetic state.


Asunto(s)
Reprogramación Celular , Cromatina/metabolismo , ADN/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Secuencia de Bases , Línea Celular , Núcleo Celular/metabolismo , ADN/química , ADN/genética , Metilación de ADN , Humanos , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/química , Factores de Transcripción de Tipo Kruppel/genética , Modelos Moleculares , Mutación , Proteína Homeótica Nanog/genética , Factor 3 de Transcripción de Unión a Octámeros/genética , Regiones Promotoras Genéticas , Dominios y Motivos de Interacción de Proteínas , Factores de Transcripción SOXB1/genética , Dedos de Zinc/genética
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