Suppression of histone deacetylation promotes the differentiation of human pluripotent stem cells towards neural progenitor cells

Juan Yang, Yu Tang, Hui Liu, Fang Guo, Jun Ni, Weidong Le

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Background: Emerging studies of human pluripotent stem cells (hPSCs) raise new prospects for neurodegenerative disease modeling and cell replacement therapies. Therefore, understanding the mechanisms underlying the commitment of neural progenitor cells (NPCs) is important for the application of hPSCs in neurodegenerative disease therapies. It has been reported that epigenetic modifications of histones play important roles in neural differentiation, but the exact mechanisms in regulating hPSC differentiation towards NPCs are not fully elucidated. Results: We demonstrated that suppression of histone deacetylases (HDACs) promoted the differentiation of hPSCs towards NPCs. Application of HDAC inhibitors (HDACi) increased the expression of neuroectodermal markers and enhanced the neuroectodermal specification once neural differentiation was initiated, thereby leading to more NPC generation. Similarly, the transcriptome analysis showed that HDACi increased the expression levels of ectodermal markers and triggered the NPC differentiation related pathways, while decreasing the expression levels of endodermal and mesodermal markers. Furthermore, we documented that HDAC3 but not HDAC1 or HDAC2 was the critical regulator participating in NPC differentiation, and knockdown of HDAC3's cofactor SMRT exhibited a similar effect as HDAC3 on NPC generation. Conclusions: Our study reveals that HDACs, especially HDAC3, negatively regulate the differentiation of hPSCs towards NPCs at an earlier stage of neural differentiation. Moreover, HDAC3 might function by forming a repressor complex with its cofactor SMRT during this process. Thus, our findings uncover an important epigenetic mechanism of HDAC3 in the differentiation of hPSCs towards NPCs.

Original languageEnglish (US)
Article number95
JournalBMC Medicine
Volume12
Issue number1
DOIs
StatePublished - 2014

Keywords

  • Histone deacetylase inhibitors
  • Histone deacetylation
  • Human pluripotent stem cells
  • Neural progenitor cells
  • Neuroectodermal specification

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Suppression of histone deacetylation promotes the differentiation of human pluripotent stem cells towards neural progenitor cells'. Together they form a unique fingerprint.

Cite this