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1.
Cell ; 173(7): 1609-1621.e15, 2018 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-29754821

RESUMEN

Diverse biological systems utilize fluctuations ("noise") in gene expression to drive lineage-commitment decisions. However, once a commitment is made, noise becomes detrimental to reliable function, and the mechanisms enabling post-commitment noise suppression are unclear. Here, we find that architectural constraints on noise suppression are overcome to stabilize fate commitment. Using single-molecule and time-lapse imaging, we find that-after a noise-driven event-human immunodeficiency virus (HIV) strongly attenuates expression noise through a non-transcriptional negative-feedback circuit. Feedback is established through a serial cascade of post-transcriptional splicing, whereby proteins generated from spliced mRNAs auto-deplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV's commitment decision, and a noise-suppression molecule promotes stabilization. This feedback mechanism for noise suppression suggests a functional role for delayed splicing in other systems and may represent a generalizable architecture of diverse homeostatic signaling circuits.


Asunto(s)
Retroalimentación Fisiológica , VIH-1/metabolismo , ARN Mensajero/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , VIH-1/genética , Humanos , Células Jurkat , Modelos Biológicos , Precursores del ARN/metabolismo , Procesamiento Postranscripcional del ARN , Empalme del ARN , Imagen de Lapso de Tiempo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética
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