Transcriptional Elongation Factor Elongin A Regulates Retinoic Acid-Induced Gene Expression during Neuronal Differentiation

• Published in: Cell reports (Cambridge) 2012-11, Vol.2 (5), p.1129-1136
• Main Authors: Yasukawa, Takashi, Bhatt, Shachi, Takeuchi, Tamotsu, Kawauchi, Junya, Takahashi, Hidehisa, Tsutsui, Aya, Muraoka, Takuya, Inoue, Makoto, Tsuda, Masayuki, Kitajima, Shigetaka, Conaway, Ronald C., Conaway, Joan W., Trainor, Paul A., Aso, Teijiro
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Differentiation - drug effects; Cell Line; Elongin; Embryo, Mammalian - metabolism; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Gene Expression Regulation - drug effects; Mice; Molecular Sequence Data; Mutation; Neurons - cytology; Neurons - metabolism; RNA Polymerase II - metabolism; Sequence Alignment; Transcription Elongation, Genetic; Transcription Factors - deficiency; Transcription Factors - genetics; Transcription Factors - metabolism; Tretinoin - pharmacology; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2012.09.031

Elongin A increases the rate of RNA polymerase II (pol II) transcript elongation by suppressing transient pausing by the enzyme. Elongin A also acts as a component of a cullin-RING ligase that can target stalled pol II for ubiquitylation and proteasome-dependent degradation. It is not known whether these activities of Elongin A are functionally interdependent in vivo. Here, we demonstrate that Elongin A-deficient (Elongin A−/−) embryos exhibit abnormalities in the formation of both cranial and spinal nerves and that Elongin A−/− embryonic stem cells (ESCs) show a markedly decreased capacity to differentiate into neurons. Moreover, we identify Elongin A mutations that selectively inactivate one or the other of the aforementioned activities and show that mutants that retain the elongation stimulatory, but not pol II ubiquitylation, activity of Elongin A rescue neuronal differentiation and support retinoic acid-induced upregulation of a subset of neurogenesis-related genes in Elongin A−/− ESCs. [Display omitted] ► RA-induced neuronal differentiation is markedly impaired in Elongin A−/− ESCs ► Formation of cranial ganglia and DRG is severely impaired in Elongin A−/− embryos ► Mutations that differentially affect the two activities of Elongin A were identified ► Elongin A’s elongation stimulatory activity is required for a subset of RA-induced genes Elongin A acts not only as a transcription elongation factor but also as a component of a ubiquitin ligase that ubiquitylates stalled RNA pol II. Here, Aso and colleagues demonstrate that Elongin A−/− mouse embryos and embryonic stem cells (ESCs) exhibit impaired neuronal development and differentiation, respectively. Moreover, they show that Elongin A mutants that are defective in RNA pol II ubiquitylation but retain the elongation stimulatory activity can rescue neuronal differentiation and retinoic acid-induced upregulation of a subset of neurogenesis-related genes in Elongin A−/− ESCs.