Transcriptional Coactivator and Chromatin Protein PC4 Is Involved in Hippocampal Neurogenesis and Spatial Memory Extinction

Amrutha Swaminathan,Hélène Delage,Snehajyoti Chatterjee,Laurence Belgarbi-Dutron,Raphaelle Cassel,Nicole Martinez,Brigitte Cosquer,Sujata Kumari,Fabien Mongelard,Béatrice Lannes,Jean-Christophe Cassel,Anne-Laurence Boutillier,Philippe Bouvet,Tapas K Kundu

doi:10.1074/jbc.m116.744169

Abstract

Although the elaborate combination of histone and non-histone protein complexes defines chromatin organization and hence regulates numerous nuclear processes, the role of chromatin organizing proteins remains unexplored at the organismal level. The highly abundant, multifunctional, chromatin-associated protein and transcriptional coactivator positive coactivator 4 (PC4/Sub1) is absolutely critical for life, because its absence leads to embryonic lethality. Here, we report results obtained with conditional PC4 knock-out (PC4(f/f) Nestin-Cre) mice where PC4 is knocked out specifically in the brain. Compared with the control (PC4(+/+) Nestin-Cre) mice, PC4(f/f) Nestin-Cre mice are smaller with decreased nocturnal activity but are fertile and show no motor dysfunction. Neurons in different areas of the brains of these mice show sensitivity to hypoxia/anoxia, and decreased adult neurogenesis was observed in the dentate gyrus. Interestingly, PC4(f/f) Nestin-Cre mice exhibit a severe deficit in spatial memory extinction, whereas acquisition and long term retention were unaffected. Gene expression analysis of the dorsal hippocampus of PC4(f/f) Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression. These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity.

Highlights

The complex eukaryotic genome is packaged in the nucleus as a dynamic DNA-protein structure, chromatin, by means of a multitude of factors
We previously found that human transcriptional coactivator 4 (PC4) is a bona fide non-histone component of chromatin that is involved in chromatin organization through its ability to interact with histones [9]
The regulation of neural gene expression by PC4, and its role in the recruitment of the REST-CoREST complex to chromatin for gene silencing indicated a possible role for PC4 in the neural system [10]

Summary

Involved in Hippocampal Neurogenesis and Spatial Memory Extinction*

Gene expression analysis of the dorsal hippocampus of PC4f/f Nestin-Cre mice revealed dysregulated expression of several neural function-associated genes, and PC4 was consistently found to localize on the promoters of these genes, indicating that PC4 regulates their expression These observations indicate that non-histone chromatin-associated proteins like PC4 play a significant role in neuronal plasticity. Nestin-Cre mice showed significant alteration in gene expression compared with the PC4ϩ/ϩ Nestin-Cre control mice, and using chromatin immunoprecipitation analysis, PC4 was found to localize on some of these gene promoters These data reveal new gene networks that could be regulated by PC4 and that are involved in neuronal activity and plasticity and likely to play a role in memory processes. These results propose a role for PC4 at the organismal level for the first time and indicate a connection between chromatin and hippocampus-dependent memory processes

Results

Number of total progeny from multiple crosses

Discussion

Absolute fold change p value

Experimental Procedures