Localized, non-random differences in chromatin accessibility between homologous metaphase chromosomes

Area of Science:

• Molecular Cytogenetics
• Epigenetics
• Genomics

Background:

• Homologous chromosomes exhibit known condensation differences during mitotic metaphase.
• This study investigates quantifiable, localized differences in condensation and DNA accessibility (DA) between homologous chromosomes.
• Reproducible DA was observed in approximately 10% of locus-specific DNA probes used in fluorescence in situ hybridization.

Purpose of the Study:

• To determine if differences in DNA accessibility (DA) between homologous chromosomes are non-random and locus-specific.
• To explore the relationship between DA and epigenetic marks.
• To investigate the heritability of DA.

Main Methods:

• Developed and hybridized 14 locus-specific DNA probes to cells from 10 individuals with distinguishable homologous chromosomes.
• Utilized 3D-structured illumination microscopy (3D-SIM) to analyze probe location and intensity.
• Analyzed interphase epigenetic marks (DNase I HS, H3K27Ac, H3K4me1) in genomic regions with and without DA.

Main Results:

• Non-random DA was observed in 8 out of 14 genomic regions, independent of imprinted domains or specific chromosomes.
• Genomic regions with DA showed significantly higher probe intensities and broader probe depth distributions compared to regions with equivalent accessibility.
• Genomic regions with equivalent accessibility were enriched for open chromatin epigenetic marks.

Conclusions:

• Localized differences in chromatin condensation and accessibility between homologous chromosomes are non-random, reproducible, and heritable.
• These differences are locus-specific but not confined to imprinted regions or specific chromosomes.
• Findings suggest that localized chromatin accessibility variations may arise from interphase epigenetic changes, impacting metaphase chromosome structure.