The Transcription Factor Sp3 Cooperates with HDAC2 to Regulate Synaptic Function and Plasticity in Neurons

Publication date: 8 August 2017
Source:Cell Reports, Volume 20, Issue 6
Author(s): Hidekuni Yamakawa, Jemmie Cheng, Jay Penney, Fan Gao, Richard Rueda, Jun Wang, Satoko Yamakawa, Oleg Kritskiy, Elizabeta Gjoneska, Li-Huei Tsai
The histone deacetylase HDAC2, which negatively regulates synaptic gene expression and neuronal plasticity, is upregulated in Alzheimer's disease (AD) patients and mouse models. Therapeutics targeting HDAC2 hold promise for ameliorating AD-related cognitive impairment; however, attempts to generate HDAC2-specific inhibitors have failed. Here, we take an integrative genomics approach to identify proteins that mediate HDAC2 recruitment to synaptic plasticity genes. Functional screening revealed that knockdown of the transcription factor Sp3 phenocopied HDAC2 knockdown and that Sp3 facilitated recruitment of HDAC2 to synaptic genes. Importantly, like HDAC2, Sp3 expression was elevated in AD patients and mouse models, where Sp3 knockdown ameliorated synaptic dysfunction. Furthermore, exogenous expression of an HDAC2 fragment containing the Sp3-binding domain restored synaptic plasticity and memory in a mouse model with severe neurodegeneration. Our findings indicate that targeting the HDAC2-Sp3 complex could enhance cognitive function without affecting HDAC2 function in other processes.

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Teaser

Yamakawa et al. demonstrate that Sp3 and HDAC2 interact to repress gene expression and negatively regulate synaptic plasticity. Inhibiting HDAC2-Sp3 binding ameliorates memory impairment in a mouse neurodegeneration model. Targeting the HDAC2-Sp3 complex might be a feasible approach to improve cognitive function without affecting other HDAC-related processes.


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