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1.
Nature ; 544(7649): 245-249, 2017 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-28379941

RESUMEN

Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.


Asunto(s)
Linaje de la Célula/genética , Reprogramación Celular/genética , Silenciador del Gen , Proteínas del Tejido Nervioso/metabolismo , Neurogénesis/genética , Neuronas/citología , Neuronas/metabolismo , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Animales , Animales Recién Nacidos , Encéfalo/citología , Encéfalo/embriología , Encéfalo/metabolismo , Células Cultivadas , Cromatina/genética , Cromatina/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Ratones , Proteínas del Tejido Nervioso/deficiencia , Especificidad de Órganos/genética , Dominios Proteicos , Receptores Notch/deficiencia , Proteínas Represoras/química , Proteínas Represoras/deficiencia , Transducción de Señal , Factor de Transcripción HES-1/deficiencia , Factores de Transcripción/deficiencia
2.
Nature ; 528(7581): 218-24, 2015 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-26659182

RESUMEN

Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.


Asunto(s)
Reprogramación Celular/genética , Factor 1 de Ensamblaje de la Cromatina/metabolismo , Animales , Células Cultivadas , Cromatina/metabolismo , Factor 1 de Ensamblaje de la Cromatina/antagonistas & inhibidores , Factor 1 de Ensamblaje de la Cromatina/genética , Regulación de la Expresión Génica/genética , Heterocromatina/metabolismo , Ratones , Nucleosomas/metabolismo , Interferencia de ARN , Transducción Genética
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