Sexual Dimorphism in Mammalian Autosomal Gene Regulation Is Determined Not Only by Sry but by Sex Chromosome Complement As Well

Abstract

Differences between males and females are normally attributed to developmental and hormonal differences between the sexes. Here, we demonstrate differences between males and females in gene silencing using a heterochromatin-sensitive reporter gene. Using "sex-reversal" mouse models with varying sex chromosome complements, we found that this differential gene silencing was determined by X chromosome complement, rather than sex. Genome-wide transcription profiling showed that the expression of hundreds of autosomal genes was also sensitive to sex chromosome complement. These genome-wide analyses also uncovered a role for Sry in modulating autosomal gene expression in a sex chromosome complement-specific manner. The identification of this additional layer in the establishment of sexual dimorphisms has implications for understanding sexual dimorphisms in physiology and disease.

Transcriptional sexual dimorphism during preimplantation embryo development and its consequences for developmental competence and adult health and disease

“…Furthermore, the effect was due to the X-chromosome complement, rather than the presence or absence of the Y-chromosome, which leads to a transcriptional regulation affecting over 1000 autosomal genes between XY and XX males or XX and XY females with 369 represented in both comparisons. Gene ontology of these sex-complement-sensitive genes highlighted differences in regulation of gene expression and RNA processing (Wijchers et al 2010), similar to the bovine microarray study (Bermejo-Alvarez et al 2010a). Taken together, it seems that while sex hormones undoubtedly play an important role in adult sexual dimorphism, sex chromosome dosage may exert a great influence and determine sexual differences in environmental epigenetic programming (Gabory et al 2009).…”

“…Interestingly, the higher level of histone acetylation seemed to be caused by testosterone exposure, but the higher level of histone methylation could not be reached in females exposed to testosterone (Tsai et al 2009). Similarly, in sex reversal mouse models, sex chromosome complement rather than sex per se determined the extent of heterochromatic silencing, which was greater in XY lymphocytes than in XX lymphocytes, irrespective of their sex (Wijchers et al 2010), in agreement with the situation observed in bovine blastocysts (Bermejo-Alvarez et al 2008b). Furthermore, the effect was due to the X-chromosome complement, rather than the presence or absence of the Y-chromosome, which leads to a transcriptional regulation affecting over 1000 autosomal genes between XY and XX males or XX and XY females with 369 represented in both comparisons.…”

“…Transcription: DNMT3A, DNMT3B, HMT1 and ILF3 (Bermejo-Alvarez et al 2008b) Gene ontology in embryos (Bermejo-Alvarez et al 2010a) and differentiated cells (Wijchers et al 2010) DNA methylation levels in embryos (Bermejo-Alvarez et al 2008b, Gebert et al 2009), ES (Zvetkova et al 2005) and differentiated cells (Tsai et al 2009, Wijchers et al 2010 Long-term effects for DNA methylation-related disorders (Fernandez-Gonzalez et al 2004, Sjoblom et al 2005, Weksberg et al 2005) Long-term effects of periconceptional methyl-deficient maternal diet (Sinclair et al 2007) Protein metabolism Gene ontology (Bermejo-Alvarez et al 2010a) Long-term effects of periconceptional low-protein maternal diet (Kwong et al 2000, Watkins et al 2008) Amino acid turnover (Sturmey et al 2010) Consequences of early embryo sexual dimorphism study associated suboptimal in vitro culture conditions with increased body weight and decreased relative brain size in males, but not in females (Sjoblom et al 2005). In humans, Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome demonstrating heterogeneous epigenetic alterations of two imprinted domains on chromosome 11p15, which originate during the preimplantation period, and it has been related with altered methylation patterns in the DMRs regulating a cluster of imprinted genes including some involved in IGF2 signaling.…”

Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome

“…In multicellulars, genes involved in regulatory networks may be another major source of dosage-sensitive genes (39). We know that the dosage of some X genes escaping XCI can modulate autosomal gene expression, although the effect is small (53). This finding suggests that many dosage-sensitive regulatory X genes may be compensated, and it would be interesting to test for dosage compensation in these genes.…”

Transcriptional sexual dimorphism in elongating bovine embryos: implications for XCI and sex determination genes

“…Several recent reports suggest that sex chromosome composition of the genome (XX or XY), irrespective of the endocrine environment, can be responsible for a large proportion of the sexual transcriptional dimorphism observed in adult tissues (Ober et al 2008, Wijchers et al 2010, especially when there is an incomplete XCI leading to an upregulation of X-linked genes in females. XCI has been suggested to greatly differ among species , and the timing of epigenetic events in ungulate models may greatly differ from the mouse.…”