Each of these marks is bidirectionally catalyzed or removed by a specific set of enzymes (Strahl and Allis, 2000). Thus, histone acetyltransferases (HATs) Anti-diabetic Compound Library in vivo catalyze the transfer

of acetyl groups to histone proteins, whereas histone deacetylases (HDACs) cause the removal of acetyl groups. Likewise, histone methylation is initiated by histone methyltransferases (HMTs) such as G9a, whereas histone demethylases (HDMs) such as LSD1 remove methylation marks (Shi et al., 2004 and Tachibana et al., 2001). Interestingly, a number of histone sites can undergo dimethylation or even trimethylation (Scharf and Imhof, 2010 and Shi and Whetstine, 2007). Finally, phosphorylation of serine or threonine residues on histone tails can be accomplished by a broad range of nuclear kinases, such as MSK-1, and can be dephosphorylated

by protein phosphatases such as protein phosphatase 1 (PP1) (Brami-Cherrier et al., IWR-1 molecular weight 2009 and Koshibu et al., 2009). Importantly, histone modifications are capable of being both gene specific within the genome and site specific within a given chromatin particle, meaning that they are in an ideal position to selectively influence gene expression. Site-specific modifications are known to directly alter chromatin state and transcription through a number of mechanisms. For example, acetylation of histone proteins is thought to activate transcription by relaxing the charged first attraction between a histone tail and DNA, thereby increasing access of transcription factors or RNA polymerase to DNA sites. Additionally, site-specific acetylation of a histone tail enables transcription factors that contain a bromodomain to bind to the histone and initiate chromatin remodeling (Dyson et al., 2001). Likewise, methylated lysines are bound by proteins with a chromodomain, although the affinity of these proteins for their respective modification is highly dependent on the overall context and presence of other modifications (Scharf and Imhof, 2010). Moreover, while some modifications such as histone acetylation or phosphorylation are generally

associated with transcriptional activation, others are more closely correlated with transcriptional repression (Barski et al., 2007 and Wang et al., 2008). Given that histone proteins can be modified at a number of sites, this raises the possibility that specific modifications could work together as a sort of “code,” which would ultimately dictate whether a specific gene was transcribed. This hypothesis, first formalized nearly a decade ago (Jenuwein and Allis, 2001, Strahl and Allis, 2000 and Turner, 2000) and more recently supported experimentally (Campos and Reinberg, 2009), suggests that certain combinations of modifications will lead to transcriptional activation, whereas others would lead to transcriptional repression.