title: BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells.
abstract: 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.
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA. Electronic address: tojingjun@yahoo.com.
authors: Jingjun
authors: J
authors: Li
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA; School of Life Science and Technology, Tongji University, Shanghai 200092, China.
authors: Jing
authors: J
authors: Ma
authors: Molecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, China.
authors: Guofeng
authors: G
authors: Meng
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Hong
authors: H
authors: Lin
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Sharon
authors: S
authors: Wu
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Jamie
authors: J
authors: Wang
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Jie
authors: J
authors: Luo
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Xiaohong
authors: X
authors: Xu
authors: Epinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK.
authors: David
authors: D
authors: Tough
authors: Epinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK.
authors: Matthew
authors: M
authors: Lindon
authors: Epinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK.
authors: Inmaculada
authors: I
authors: Rioja
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Jing
authors: J
authors: Zhao
authors: Molecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, China.
authors: Hongkang
authors: H
authors: Mei
authors: Epinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UK.
authors: Rab
authors: R
authors: Prinjha
authors: Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USA.
authors: Zhong
authors: Z
authors: Zhong
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D007150:Immunohistochemistry; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C518476:Brd3 protein, mouse; C486694:Brd4 protein, mouse
keywords: BET bromodomain; Epigenetics; Gliogenesis; I-BET; JQ-1; Neural progenitor cells; Neurogenesis; Small molecule inhibitor