Journal of Molecular Neuroscience 47 Volume 31, 2007 *Author to whom all correspondence and reprint requests should be addressed. E-mail: christopher_winrow@merck.com Distribution of Histone Deacetylases 1–11 in the Rat Brain Ron S. Broide, 1 Jeff M. Redwine, 1 Najla Aftahi, 1 Warren Young, 1 Floyd E. Bloom, 1 and Christopher J. Winrow* ,2 1 Neurome, La Jolla, CA 92037; and 2 Merck Research Laboratories, West Point, PA 19486 Received May 15, 2006; Accepted June 3, 2006 Abstract Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling molecules is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyl transferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurodegeneration. We initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1–11) (classes I, II, and IV) throughout the rat brain using high-resolution in situ hybridization (ISH) and imaging technology. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addition, immunohistochemistry was performed on these samples to separately examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled standards and thereby enabled semiquantitative analysis of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examining the roles of specific HDACs in the brain and the development of future modulators of HDAC activity. DOI 10.1385/JMN/31:01:47 Index Entries: Histone deacetylase; gene expression; brain; transcription. Introduction Chromatin remodeling by modulation of histone acetylation states is carried out by histone deacetylases (HDACs) and histone acetyl transferases (HATs) in association with multiprotein complexes (for review, see Marks et al., 2003; Shabbeer and Carducci, 2005). In addition to regulating transcription through modi- fying the acetylation state of histones, acetylation is being recognized as an important post-translational modification for many nonhistone proteins (Bereshchenko et al., 2002; Haggarty et al., 2003; Vaghefi and Neet, 2004). The critical roles of the HDAC and HAT family members in transcription and signal Journal of Molecular Neuroscience Copyright © 2007 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN0895-8696/07/31:47–58/$30.00 JMN (Online)ISSN 1558-6804 DOI 10.1385/JMN/31:01:47 ORIGINAL ARTICLE transduction are quickly emerging. In a similar manner, the contribution of aberrant acetylation in a host of disease states is being recognized. The role of HDACs and their increased or decreased acti- vities have been implicated in multiple indications, including cancer (Choi et al., 2001; Richon et al., 2001; Johnstone, 2002), cardiovascular disease (Ito et al., 2005; Lin, 2005), asthma (Ito et al., 2002; Choi et al., 2005), and other disease states (Chiurazzi et al., 1999; Alarcon et al., 2004). By far, the most attention has been focused on the use of HDAC modulators for cancer, with several late-stage clinical trials ongoing (for review, see Marks et al., 2004; Acharya et al., 2005; Kelly et al., 2005; Moradei et al., 2005). The application