Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain

Abstract

Jarid1c, an X-linked gene coding for a histone demethylase, plays an important role in brain development and function. Notably, JARID1C mutations cause mental retardation and increased aggression in humans. These phenotypes are consistent with the expression patterns we have identified in mouse brain where Jarid1c mRNA was detected in hippocampus, hypothalamus, and cerebellum. Jarid1c expression and associated active histone marks at its 5'end are high in P19 neurons, indicating that JARID1C demethylase plays an important role in differentiated neuronal cells. We found that XX mice expressed Jarid1c more highly than XY mice, independent of their gonadal types (testes versus ovaries). This increased expression in XX mice is consistent with Jarid1c escape from X inactivation and is not compensated by expression from the Y-linked paralogue Jarid1d, which is expressed at a very low level compared to the X paralogue in P19 cells. Our observations suggest that sex-specific expression of Jarid1c may contribute to sex differences in brain function.

Figure 1. Expression of Jarid1c in adult mouse brain using in situ hybridization with riboprobes.

Examples of sections from an adult female brain are shown. Specific brain regions with higher expression levels are the olfactory bulb (OB), piriform cortex (Pir), habenula (H), hypothalamus such as suprachiasmatic nucleus (SCN), ventromedial hypothalamic nucleus (VMH) and arcuate nucleus (Arc), hippocampus (CA), and cerebellum (Cb). ac: anterior commissure; Arc: arcuate nucleus; AV: anteroventral thalamic nucleus; BST: bed nucleus of the stria terminalis; C: cortex; CA: CA1 and CA3 subfields of hippocampus; DG: dentate gyrus; EPI: external plexiform layer of olfactory bulb; InC: interstitial nucleus Cajal; M: mammillary nucleus; MPOA: medial preoptic area; Pir: piriform cortex; Pn: pontine nuclei; PVA: paraventricular thalamic nucleus; PVN: paraventricular nucleus; St: striatum; TS: Triangular septal nucleus.

Figure 2. Jarid1c expression level depends on the number of X chromosomes, not on gonadal sex.

Example of a northern blot containing mRNA from brains of XX females, XY⁻ females, XXSry males and XY⁻ Sry males hybridized to a Jarid1c probe. Hybridization to a probe for Actb (Actin) was used as a loading control. The graph below shows the relative expression of Jarid1c versus Actb (β-actin) quantified by densitometry. XXSry males and XX females had significantly higher Jarid1c expression than XY⁻ Sry males and XY⁻ females, with no difference between mice possessing testes or ovaries.

Figure 3. Expression of Jarid1c in adult liver and neonatal brain is similar between males and females.

Example of a northern blot containing mRNA from four neonatal brain samples and four liver samples from males and females hybridized to a probe for Jarid1c. Hybridization to a probe for Gapdh was used as a loading control.

Figure 4. Expression of Jarid1c in P19 neurons is associated with active chromatin marks.

Ratios between the bound and input chromatin fractions from P19 stem cells (solid lines) and P19 neurons (dashed line) were measured by Q-PCR at three sites around Jarid1c transcription start site indicated on the Y axis. Histone H3 acetylation at lysine 9 and lysine 14 (H3ac), H3 di-methylation at lysine 4 (H3K4me2) and to a lesser extent H4 acetylation at lysine 16 were enriched at the 5′ end of Jarid1c especially in P19 neurons.