GTMB 7 - Gene Therapy & Molecular Biology

Spencer and Davie: Dynamic histone acetylation and its involvement in transcription30 nm fiber is maintained by the N terminal tails (Davieand Spencer, 2001).The chromatin fiber becomes moderately folded bythe H3 and H4 N terminal tails at physiological ionicstrength. However, the N terminal tails of the four corehistones are required for the chromatin fiber to undergoextensive folding (Tse and Hansen, 1997; Logie et al,1999). At low ionic strength, the chromatin fiber assumesa three-dimensional irregular shape that is stabilized by theglobular domain of H1 and either the H1 tails or the H3 Nterminal tail (Zlatanova et al, 1998; Leuba et al, 1998a).The N terminal tails from histones H2A, H2B and H4 donot have the same effect as H3 on the chromatin fiber.However, the N terminal tail of H3 is 44 amino acids long,whereas histones H4, H2B and H2A have N terminal tailsthat are only 26, 32, and 16 amino acids long, respectively.As a result, the N terminal tail of histone H3 can extendover a significantly larger portion of linker DNAcompared to the other core histones (Leuba et al, 1998b).The H3 N terminus is also positioned close to the pointwhere linker DNA enters and exits the nucleosome, and,therefore, it can undergo extensive interactions with thelinker DNA (Zlatanova et al, 1998).The chromatin fibers within a cell interdigitate withneighboring fibers into a higher order fibrous mass thatimpedes the access of transcription factors to their targetsequences, thereby preventing transcription initiation(Schwarz et al, 1996). At physiological ionic strength, theinteraction of these neighboring fibers with one another ispartly dependent on either the H2A and H2B or the H3and H4 core histone N terminal tails (Davie and Spencer,2001). These fibrous masses are then further organizedinto compact chromosome territories within interphasenuclei (Verschure et al, 1999).In addition to binding linker DNA, the histone Nterminal tails are capable of interacting with other histonesand non-histone chromosomal proteins. The N terminus ofH4 binds to the H2A-H2B dimer of neighboringnucleosomes, and, as such, is thought to assist inchromatin folding (Luger et al, 1997). In yeast, thetranscriptional repressors Sir3, Sir4, and Ssn6/Tup1interact with the H3 and H4 N terminal domains, causingthe associated chromatin to become transcriptionallyrepressed (Grunstein, 1998). Likewise, the DrosophilaGroucho and its mammalian homologues bind to the Nterminal domain of H3 and repress transcription (Palapartiet al, 1997; Fisher and Caudy, 1998). These domains alsointeract with non-histone proteins such as HMG-14 andHMG-17 that promote the unfolding of higher orderchromatin structures (Bustin, 1999).III. Acetylation of the histone Nterminal tailsThe N terminal tails can undergo a series of posttranslationalmodifications at specific amino acidsincluding acetylation, phosphorylation, ubiquitination andmethylation (Spencer and Davie, 1999) (Figure 1). Themost extensively studied of these modifications is dynamicacetylation, a reversible process catalyzed byacetyltransferases and deacetylases which mediate thetransfer of acetyl groups on to and off of the ε-aminogroup of N terminal lysine residues, respectively (Kuo andAllis, 1998).Figure 1. General structure of the core histones and their sites of post-translational modifications. The central globular domain ofeach histone is depicted as a circle with the N and C terminal tails extending towards the left and right sides, respectively. Me, Ac, P, andUb represent methylation, acetylation, phosphorylation, and ubiquitination, respectively. HAT A (histone acetyltransferase) and HDAC(histone deacetylase) represent the enzymes that catalyze the reversible acetylation of lysine residues along the histone N terminal tails.H3 kinase and PP1 (protein phosphatase 1) represent the enzymes responsible for the reversible phosphorylation of H3 serine residue.2