BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells

Stem Cell Research

Hong Lin¹  Jing Ma¹  Jie Luo¹  Inmaculada Rioja¹  David Tough¹  Hongkang Mei¹  Zhong Zhong¹  Sharon Wu²  Xiaohong Xu³  Guofeng Meng³  Jing Zhao³  Matthew Lindon³  Jingjun Li³  Jamie Wang³  Rab Prinjha³ 

[1] Cambridge, MA02139, USA;Molecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, China;Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China;

关键词: Neurogenesis;    Gliogenesis;    Neural progenitor cells;    BET bromodomain;    Small molecule inhibitor;    I-BET;    JQ-1;    Epigenetics;   

DOI  :  10.1016/j.scr.2016.07.006

来源: DOAJ

【 摘 要 】

Neural stem cells and progenitor cells (NPCs) are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases. However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. To identify novel chemical entities/targets for neurogenesis, we had established a NPC phenotypic screen assay and validated it using known small-molecule neurogenesis inducers. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis. BET bromodomain proteins, Brd2, Brd3, and Brd4 were found to be downregulated in NPCs upon differentiation, while their levels remain unaltered in proliferating NPCs. Consistent with the pharmacological study using bromodomain selective inhibitor (+)-JQ-1, knockdown of each BET protein resulted in an increase in the number of neurons with simultaneous reduction in both astrocytes and oligodendrocytes. Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases.

【 授权许可】

Unknown