Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation

Sang Hoon Yi, Xi Biao He, Yong Hee Rhee, Chang Hwan Park, Takumi Takizawa, Kinichi Nakashima, Sang Hun Lee

研究成果: Contribution to journalArticle査読

37 被引用数 (Scopus)

抄録

Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Coexpression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoRESTHdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development.

本文言語英語
ページ(範囲)761-772
ページ数12
ジャーナルDevelopment (Cambridge)
141
4
DOI
出版ステータス出版済み - 2 15 2014
外部発表はい

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 発生生物学

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