Sex-Specific Differences in Expression of Histone DemethylasesUtxandUtyin Mouse Brain and Neurons

Abstract

Although X inactivation is thought to balance gene expression between the sexes, some genes escape inactivation, potentially contributing to differences between males and females. Utx (ubiquitously transcribed tetratricopeptide repeat gene on X chromosome) is an escapee gene that encodes a demethylase specific for lysine 27 of histone H3, a mark of repressed chromatin. We found Utx to be expressed higher in females than in males in developing and adult brains and in adult liver. XX mice had a higher level of Utx than XY mice, regardless of whether they had testes or ovaries, indicating that the sexually dimorphic gene expression was a consequence of the sex chromosome complement. Females had significantly higher levels of Utx than males in most brain regions except in the amygdala. The regional expression of the Y-linked paralogue Uty (ubiquitously transcribed tetratricopeptide repeat gene on Y chromosome) was somewhat distinct from that of Utx, specifically in the paraventricular nucleus of the hypothalamus (high Uty) and the amygdala (high Utx), implying that the two paralogues may be differentially regulated. Higher expression of Utx compared with Uty was detected in P19 pluripotent embryonic carcinoma cells as well as in P19-derived neurons. This transcriptional divergence between the two paralogues was associated with high levels of histone H3 lysine 4 dimethylation at the Utx promoter and of histone H4 lysine 16 acetylation throughout the gene body, which suggests that epigenetic mechanisms control differential expression of paralogous genes.

Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease

“…Moreover, although UTX is considered to escape X chromosome inactivation (45), we did not detect a difference in podocyte UTX levels between male and female patients. This observation is consistent with an earlier report that UTX expression from the inactive X chromosome is significantly lower than it is from the active X chromosome (46). Although UTX and Jmjd3 are similar in their JmjC catalytic domains, they are also structurally distinct.…”

The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia

“…Previous studies demonstrated that UTX can escape chromosome X-inactivation in normal female tissues, 23,37,38 and accordingly, shows higher expression in female embryonic stem cells and female tissues derived from brain, liver, neurons, and sexual organs in comparison with their male counterpart. [36][37][38] The fact that UTX escapes chromosome X-inactivation in normal cells has important implications for gender-related tumor susceptibility. Indeed, given the previously established role for UTX as a tumor suppressor in human cancer, inactivation of only one single UTX copy in males will contribute to tumor development.…”

Sex effect on presenilins expression in post-natal rat brain

“…These receptors in turn influence gene expression by acting in complexes with co-activators and co-repressors, several of which have enzymatic activities modifying histones status [28]. Interestingly, both histone-acetylation and methylation are sexually dimorphic in the developing cortex and hippocampus of the mouse during the first post-natal week [29].…”