Sex-specific multi-level 3D genome dynamics in the mouse brain.

Area of Science:

• Neuroscience
• Genomics
• Epigenetics

Background:

• The female mammalian brain shows plasticity driven by sex hormones during the reproductive period.
• Chromatin dynamics are increasingly recognized as key regulators of this plasticity.
• The impact of ovarian hormones on higher-order chromatin organization in post-mitotic neurons remains largely unexplored.

Purpose of the Study:

• To investigate the influence of ovarian hormones on the 3D genome organization in post-mitotic neurons in vivo.
• To map the dynamic changes in 3D chromatin structure across the oestrous cycle and between sexes in mice.

Main Methods:

• 3D genome mapping (e.g., Hi-C) was performed on ventral hippocampal neurons from mice.
• Analyses were conducted across different stages of the oestrous cycle and between male and female subjects.

Main Results:

• Female 3D genome organization exhibits cyclical dynamism, particularly in estrogen response elements, X chromosome compartments, CTCF loops, and enhancer-promoter interactions.
• Increasing estrogen levels correlate with the female 3D genome becoming more similar to the male 3D genome.
• Cyclical enhancer-promoter interactions are partially linked to gene expression and are enriched for genes and pathways relevant to brain disorders.

Conclusions:

• This study reveals novel, dynamic 3D genome organization in the female brain influenced by the reproductive cycle.
• These findings highlight unique regulatory mechanisms in the female brain relevant to female-specific gene regulation, neuroplasticity, and disease susceptibility.