Untitled

Abstract

The family of human histone genes consists of replication-dependent and independent subtypes. The replication-independent histone genes, also known as variants, give rise to distinct mRNAs, whose expression is regulated depending on the growth state of the cell, tissue type and developmental stage. In turn, the histone variants are differentially synthesized and modified by acetylation. Consequently, chromatin structure is altered resulting in complex changes in gene expression. The high conservation among histone protein subtypes suggests that they are indispensable. In addition, conservation of the positions of acetylation within subtypes suggests that the location of these sites is functionally important for the eukaryotic cell. For example, the structures of transcriptionally active and repressed chromatin are different depending on the acetylation state of histone proteins [1-3]. In addition, transcriptionally active and repressed chromatin contains distinct histone variants [4]. Specialized histone variants are targeted to the centromere of the chromosome, where they are essential for chromosome segregation [5]. Other specialized histones exist that are essential for development [6]. Changes in histone acetylation have been implicated in the down-regulation of a tumour suppressor gene in human breast cancer [7]. Acetylation also plays an important role in X chromosome inactivation as well as hormone-mediated transcriptional regulation [8, 9]. We propose here a novel model for histone variant gene regulation at the post-transcriptional level, which provides the groundwork to define the pathways regulating the synthesis of these variants.

The Many Tales of a Tail: Carboxyl-Terminal Tail Heterogeneity Specializes Histone H2A Variants for Defined Chromatin Function

“…Although post-translational modification, particularly acetylation, remains the most documented aspect of the epigenetic regulation of chromatin, the incorporation of histone variants into nucleosomes also has significant impacts for gene expression, repair cascades, and meiotic events (12). Histone variants are nonallelic, mRNA-polyadenylated isoforms of major histones, which display localized positioning and are synthesized at varying points throughout development and the cell cycle (15,16). Differential expression patterns of these proteins enable the deposition of specialized nucleosomes during cellular events outside the window of genomic duplication in the S phase, and suggest that the exchange of histone variants may be an active process throughout the cell cycle and quiescence.…”

Structural Characterization of MacroH2A Containing Chromatin

“…Histone variants are nonallelic isoforms that replace major histones within specialized chromatin domains. In humans, the genes of these subtypes are absent from the canonic histone gene cluster and are expressed outside of the of S phase of the cell cycle ( , ). This suggests that the functions of these gene products are not exclusive to the structural packaging of newly replicated DNA and are important for constitutive regulatory events.…”

AT1 Receptor Induced Alterations in Histone H2A Reveal Novel Insights into GPCR Control of Chromatin Remodeling

“…In previous studies Hirota et al , 2005, found that the phosphorylation of histone H3 at Ser-10 negatively regulated the binding of HP1α to the adjacent methylated Lys-9 of histone H3. Based on their study of histone H3 modifications, these authors proposed the binary switch hypothesis [26]. We propose that dephosphorylation of the N-terminal H2A1Sp may induce H2A125Kme1 modification at the C-terminus.…”

“…These isoforms are products of various genes that encode slightly different primary sequences shown in Fig. 7 [26], [27]. The human genome encodes four replacement H2A histones; H2AZ, macroH2A, H2A-Bbd, and H2AX.…”

“…This would provide a mechanism for regulating genes through variegation of chromatin domains and alter higher order chromatin structure. The differences in the sequence of histone isoforms affects chromatin function by providing binding sites to other histone isoforms, modifying enzymes or transcription factors and thus may alter nucleosome stability [26].…”