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Wiedemann, Sonja (2010): Identification and Characterization of Two Novel Primate-specific Histone H3 Variants, H3.X and H3.Y. Dissertation, LMU München: Fakultät für Biologie



Chromatin is the packaged form of DNA in the eukaryotic nucleus, with the nucleosome as its basic unit. The nucleosome consists of DNA, wrapped around a histone octamer which is comprised of two copies of each of the four core histones H2A, H2B, H3 and H4. To allow DNA-related processes to occur, access to the DNA has to be regulated. One regulatory mechanism is the exchange of the canonical core histones by one of their replacement variants. Thus far, five members of the histone H3 family have been described: H3.1, H3.2, H3.3, testis-specific tH3 and centromere-specific CENP-A. Searching the database, we have recently identified two novel histone H3 variant genes on human chromosome 5, now termed H3.X and H3.Y. In my PhD thesis, I have analyzed their expression patterns, characterized their mRNA as well as their protein products and investigated their potential function(s). H3.X and H3.Y constitute primate-specific genes which have been found, in addition to humans, also in the chimpanzee and the macaque, but not in other mammals or even lower eukaryotes. H3.X and especially H3.Y mRNA is expressed at low but significant levels in the human osteosarcoma cell line U2OS and in some human bone, breast, lung and ovary tumor tissues, as well as in testis and certain areas of the brain. Tagged H3.X and H3.Y proteins behave similar to H3.1, H3.2 and H3.3 in their nuclear localization and stable incorporation into chromatin. However, in contrast to H3.1 and H3.3, novel H3 variants primarily form heterotypic nucleosomes. Endogenous H3.Y protein is expressed in a small number of U2OS cells (<0.1%), localizes to the nucleus and constitutes a stable chromatin component. The number of H3.Y-expressing U2OS cells can be increased by specific stress conditions, such as nutritional stress paired with high cell density. Matching its expression pattern in U2OS cells, H3.X and/or H3.Y protein(s) have also been observed in a small subpopulation of neurons in the human hippocampus. H3.Y has an influence on the expression of certain genes, most of them being implicated in regulating the cell cycle and chromatin structure. In line with this finding, knockdown of H3.X and H3.Y impairs cell growth. In conclusion, the results of this work show that H3.Y (and maybe H3.X) are novel primatespecific histone H3 variants which play a role in cell cycle regulation. Their expression is induced by certain stress stimuli and their presence in brain and testis suggests a potential role in primate-specific brain functions and speciation.