BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells
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 replacem...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-09-01
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| Series: | Stem Cell Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1873506116300782 |
| _version_ | 1819013999318007808 |
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| author | Jingjun Li Jing Ma Guofeng Meng Hong Lin Sharon Wu Jamie Wang Jie Luo Xiaohong Xu David Tough Matthew Lindon Inmaculada Rioja Jing Zhao Hongkang Mei Rab Prinjha Zhong Zhong |
| author_facet | Jingjun Li Jing Ma Guofeng Meng Hong Lin Sharon Wu Jamie Wang Jie Luo Xiaohong Xu David Tough Matthew Lindon Inmaculada Rioja Jing Zhao Hongkang Mei Rab Prinjha Zhong Zhong |
| author_sort | Jingjun Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T02:08:52Z |
| format | Article |
| id | doaj.art-b0fe28873175464cb62a89e4c26a66ef |
| institution | Directory Open Access Journal |
| issn | 1873-5061 1876-7753 |
| language | English |
| last_indexed | 2024-12-21T02:08:52Z |
| publishDate | 2016-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Research |
| spelling | doaj.art-b0fe28873175464cb62a89e4c26a66ef2022-12-21T19:19:26ZengElsevierStem Cell Research1873-50611876-77532016-09-0117221222110.1016/j.scr.2016.07.006BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cellsJingjun Li0Jing Ma1Guofeng Meng2Hong Lin3Sharon Wu4Jamie Wang5Jie Luo6Xiaohong Xu7David Tough8Matthew Lindon9Inmaculada Rioja10Jing Zhao11Hongkang Mei12Rab Prinjha13Zhong Zhong14Regenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USARegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USAMolecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, ChinaRegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USARegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USARegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USARegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USARegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USAEpinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UKEpinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UKEpinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UKRegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USAMolecular Discovery Research, Platform Technologies and Science, GlaxoSmithKline R&D, Shanghai 201203, ChinaEpinova DPU, GlaxoSmithKline R&D, Stevenage SG1 2NY, UKRegenerative Medicine DPU, GlaxoSmithKline R&D, Shanghai 201203, China; Cambridge, MA02139, USANeural 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.http://www.sciencedirect.com/science/article/pii/S1873506116300782NeurogenesisGliogenesisNeural progenitor cellsBET bromodomainSmall molecule inhibitorI-BETJQ-1Epigenetics |
| spellingShingle | Jingjun Li Jing Ma Guofeng Meng Hong Lin Sharon Wu Jamie Wang Jie Luo Xiaohong Xu David Tough Matthew Lindon Inmaculada Rioja Jing Zhao Hongkang Mei Rab Prinjha Zhong Zhong BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells Stem Cell Research Neurogenesis Gliogenesis Neural progenitor cells BET bromodomain Small molecule inhibitor I-BET JQ-1 Epigenetics |
| title | BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| title_full | BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| title_fullStr | BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| title_full_unstemmed | BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| title_short | BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| title_sort | bet bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells |
| topic | Neurogenesis Gliogenesis Neural progenitor cells BET bromodomain Small molecule inhibitor I-BET JQ-1 Epigenetics |
| url | http://www.sciencedirect.com/science/article/pii/S1873506116300782 |
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