Abstract
BackgroundSexual dimorphism in brain gene expression has been recognized in several animal species. However, the relevant regulatory mechanisms remain poorly understood. To investigate whether sex-biased gene expression in mammalian brain is globally regulated or locally regulated in diverse brain structures, and to study the genomic organisation of brain-expressed sex-biased genes, we performed a large scale gene expression analysis of distinct brain regions in adult male and female mice.ResultsThis study revealed spatial specificity in sex-biased transcription in the mouse brain, and identified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampus and 31 in the eye. Genes located on sex chromosomes were consistently over-represented in all brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealed Y-encoded male-biased transcripts and X-encoded female-biased transcripts known to escape X-inactivation. In addition, we identified novel coding and non-coding X-linked genes with female-biased expression in multiple tissues. Interestingly, the chromosomal positions of all of the female-biased non-coding genes are in close proximity to protein-coding genes that escape X-inactivation. This defines X-chromosome domains each of which contains a coding and a non-coding female-biased gene. Lack of repressive chromatin marks in non-coding transcribed loci supports the possibility that they escape X-inactivation. Moreover, RNA-DNA combined FISH experiments confirmed the biallelic expression of one such novel domain.ConclusionThis study demonstrated that the amount of genes with sex-biased expression varies between individual brain regions in mouse. The sex-biased genes identified are localized on many chromosomes. At the same time, sexually dimorphic gene expression that is common to several parts of the brain is mostly restricted to the sex chromosomes. Moreover, the study uncovered multiple female-biased non-coding genes that are non-randomly co-localized on the X-chromosome with protein-coding genes that escape X-inactivation. This raises the possibility that expression of long non-coding RNAs may play a role in modulating gene expression in domains that escape X-inactivation in mouse.
Highlights
Sexual dimorphism in brain gene expression has been recognized in several animal species
Emerging evidence indicates that the regulatory pathways underlying sexual differentiation result in phylogenetically widespread transcriptional sex-bias in the brain of organisms ranging from D. melanogaster to humans [1]
Our data indicate that the degree of sex-biased gene expression varies between distinct brain structures in adult mouse brain
Summary
Sexual dimorphism in brain gene expression has been recognized in several animal species. The mechanisms by which sex differences in the brain are established and controlled during development are not understood in detail, but sex hormones clearly play major roles. Sex hormones are not sufficient to explain all sex differences, and genes encoded in the sex chromosomes are known to be important [4] These genes include male-specific Y-encoded genes as well as female-biased X-encoded genes that escape the dosage compensating inactivation of one X-chromosome in females. Only a few genes that escape X-inactivation have been identified [5,6,7,8,9] These genes are known to produce female-biased expression very early during development [10], but the molecular control mechanisms remain mostly unknown
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