Growth regulation of human variant histone genes and acetylation of the encoded proteins

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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.