HDAC1 Regulates Neuronal Differentiation.

Vanesa Nieto-Estevez,Jingfei Zhu,Rawan Serena Kassim,Marissa Olga Coppin,Jenny Hsieh,Adebayo Olukayode Adeyeye,Gopakumar Changarathil

doi:10.3389/fnmol.2021.815808

Abstract

In adult hippocampal neurogenesis, chromatin modification plays an important role in neural stem cell self-renewal and differentiation by regulating the expression of multiple genes. Histone deacetylases (HDACs), which remove acetyl groups from histones, create a non-permissive chromatin that prevents transcription of genes involved in adult neurogenesis. HDAC inhibitors have been shown to promote adult neurogenesis and have also been used to treat nervous system disorders, such as epilepsy. However, most HDAC inhibitors are not specific and may have other targets. Therefore, it is important to decipher the role of individual HDACs in adult hippocampal neurogenesis. HDACs 1, 2, and 3 have been found expressed at different cellular stages during neurogenesis. Conditional deletion of HDAC2 in neural stem cells impairs neuronal differentiation in adult hippocampus. HDAC3 supports proliferation of adult hippocampal neural stem/progenitor cells. The role of HDAC1 in adult neurogenesis remains still open. Here, we used a conditional knock-out mouse to block HDAC1 expression in neural stem cells (Nestin+ cells) during hippocampal neurogenesis. Our results showed that both HDAC1 and HDAC2 are expressed in all cellular stages during hippocampal neurogenesis. Moreover, we found that deletion of HDAC1 by viral infection of neural stem cells is sufficient to compromise neuronal differentiation in vitro. However, we were unable to reduce the expression of HDAC1 in vivo using Nestin-CreERT2 mice. Understanding the role of HDAC1 may lead to ways to control stem cell proliferation and neuronal regeneration in the adult hippocampus, and to more specific HDAC therapeutics for neurological disorders.

Highlights

Chromatin modifications have been shown to be critical during brain development by regulating gene expression in a precise spatial and temporal manner
We studied the expression of HDAC1 and HDAC2 at different stages during adult hippocampal neurogenesis
We found a wide expression of HDAC1 in the dentate gyrus (DG) using two different antibodies (Supplementary Figure 1)

Summary

Introduction

Chromatin modifications have been shown to be critical during brain development by regulating gene expression in a precise spatial and temporal manner. One such modification is acetylation in the N-terminal tails of histones H3 and H4, which reduces the affinity of the histones to the DNA, opens the chromatin and promotes gene expression. VPA has been shown to promote both neurogenesis and gliogenesis (Hsieh et al, 2004; Lee et al, 2016) The limitation of these HDAC inhibitors is the lack of specificity in their actions affecting multiple genes including non-histone proteins (Milazzo et al, 2020). Some efforts have been made to decipher the role of individual HDACs in neurogenesis

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Results

Conclusion