Histone acetylation and gene expression in neural cells - probed by small molecule modulators

Abstract

Nucleus, is a general phenomenon across eukaryotes. DNA is packaged as a nucleoprotein complex called ‘Chromatin’. Chromatin is also the physiological template for all nuclear processes involving genomic DNA, including transcription by RNA polymerase II (Pol II). The structural unit of chromatin, the nucleosome, comprises 147 bp of DNA wrapped around an octamer of core histone proteins (two copies each of H2A, H2B, H3, and H4) in ~1.7 turns (Figure 1.1) (Richmond and Davey, 2003). However the wrapping of DNA into chromatin also limits the accessibility of the DNA to factors involved in these processes, thus implicating regulation at a higher scale, making it more accessible in a spatio-temporal manner, to overcome the hindrances to physiological processes that are DNA templated. It is immediately observed that chromatin exists in multiple, functionally distinct structural states, that are defined by their protein composition and level of compaction that directly influences one pivotal process, Transcription (e.g., transcriptionally active euchromatin and transcriptionally repressed heterochromatin (Horn and Peterson, 2002; Woodcock and Dimitrov, 2001). The dynamic interconversion between these different chromatin states can play an important role in transcriptional regulation (Horn and Peterson, 2002; Woodcock and Dimitrov, 2001). The establishment of distinct chromatin domains can be achieved through (1) ATP dependent chromatin remodeling factors (2) specific covalent modification of histones (e.g., acetylation, methylation), (3) nucleosome assembly with histone variants (e.g., H2A.Z, CENP-A), (4) Involvement of RNAs in gene silencing and heterochromatinization or (5) incorporation of nucleosome binding non-core histone proteins, such as the linker histone H1, the heterochromatin-associated protein HP1, poly(ADP-ribose) polymerase-1 (PARP-1) and PC4 (Brown, 2003; Horn and Peterson, 2002; Kellum, 2003; Kim et al. 2004; Das et al. 2006) (Figure 1). The formation and disruption of higher-order chromatin structures is regulated by the histone-modifying enzymes (e.g., acetyltransferases, deacetylases) and also by chromatin remodeling complexes (e.g., SWI/SNF family). These factors act locally to modify individual nucleosomes at specific gene promoters (Horn and Peterson, 2002). Thus, chromatin structure and chromatin templated activity is modulated by its constituent proteins and a diverse group of regulatory enzymes.