Classical genetic experiments and emerging genomic results indicate that regulatory genes exhibit a dosage sensitive balance, which, if upset, causes changes in target gene expression. The major type of dosage effect on gene expression is an inverse correlation with the dosage of the varied chromosomal segment. Previous results are consistent with an inverse effect component to the mechanism of dosage compensation, the process that equalizes gene expression of the X chromosomes despite a difference in dosage between the sexes. Data also suggest that a similar type of up-regulation of the autosomes in Drosophila has been muted during the evolution of the sex chromosomes by the sequestration of a histone acetylase to the X via the action of the male specific lethal (MSL) complex, which is localized to the X chromosome in males. In the proposed work, specific aims will address the relationship of chromatin modification and gene expression when different components of the MSL complex are targeted to reporter constructs on the X chromosome and the autosomes. These experiments will provide insight into the activating and inhibitory properties of the MSL complex. The nature of the override process of histone acetylation on gene expression by the MSL complex will also be examined. Histone acetylation in many situations tends to open the chromatin for access by transcription factors. However, previous evidence suggests that the MSL complex will override the impact of histone acetylation on gene expression. Experiments will be conducted to elucidate the nature of this novel process by targeting proteins thought to be involved, either singly or in combinations, to reporter transgenes on the X and autosomes in males and females of various genotypes.
The relevance of the proposed project to public health is that it will contribute to an understanding of genomic regulatory balance. Changes in chromosomal dosage are major contributors birth defects. The single active X chromosome in humans of both males and females must be up-regulated for viability. The proposed project will examine the type of mechanism responsible for this up-regulation.
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|Birchler, James A (2014) Facts and artifacts in studies of gene expression in aneuploids and sex chromosomes. Chromosoma 123:459-69|
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|Sun, Lin; Fernandez, Harvey R; Donohue, Ryan C et al. (2013) Male-specific lethal complex in Drosophila counteracts histone acetylation and does not mediate dosage compensation. Proc Natl Acad Sci U S A 110:E808-17|
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|Sun, Lin; Johnson, Adam F; Li, Jilong et al. (2013) Differential effect of aneuploidy on the X chromosome and genes with sex-biased expression in Drosophila. Proc Natl Acad Sci U S A 110:16514-9|
|Birchler, James A; Veitia, Reiner A (2012) Gene balance hypothesis: connecting issues of dosage sensitivity across biological disciplines. Proc Natl Acad Sci U S A 109:14746-53|
|Birchler, James; Sun, Lin; Fernandez, Harvey et al. (2011) Re-evaluation of the function of the male specific lethal complex in Drosophila. J Genet Genomics 38:327-32|
|Veitia, Reiner A; Birchler, James A (2010) Dominance and gene dosage balance in health and disease: why levels matter! J Pathol 220:174-85|
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