TY - JOUR
T1 - Suppression of histone deacetylation promotes the differentiation of human pluripotent stem cells towards neural progenitor cells
AU - Yang, Juan
AU - Tang, Yu
AU - Liu, Hui
AU - Guo, Fang
AU - Ni, Jun
AU - Le, Weidong
N1 - Funding Information:
We thank Dr. Ying Jin, the Director of the Key Laboratory of Stem Cell Research of the Institute of Health Sciences, Chinese Academy of Sciences, for kindly providing the N-iPSC-1 hiPSC line. This study was supported by grants from the Ministry of Science and Technology of China (2010CB945201 and 2011CB510003) and the Shanghai Municipal Commission for Science and Technology (11JC1414301).
Publisher Copyright:
© 2014 Yang et al.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Histone deacetylase inhibitors
KW - Histone deacetylation
KW - Human pluripotent stem cells
KW - Neural progenitor cells
KW - Neuroectodermal specification
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U2 - 10.1186/s12915-014-0095-z
DO - 10.1186/s12915-014-0095-z
M3 - Article
C2 - 25406762
AN - SCOPUS:84923352107
VL - 12
JO - BMC Medicine
JF - BMC Medicine
SN - 1741-7015
IS - 1
M1 - 95
ER -