Autosomal allelic inactivation at loci with variable replication timing and dosage sensitivity

Area of Science:

• Epigenetics
• Genomics
• Cellular Biology

Background:

• Autosomal genes exhibit monoallelic expression and asynchronous replication, similar to imprinted genes and those under allelic exclusion.
• Inactivation/Stability Centers (I/SCs) are autosomal loci with epigenetic regulation of allelic expression and replication timing, comparable to X chromosome inactivation.

Purpose of the Study:

• To characterize over 100 autosomal loci (I/SCs) with allele-specific epigenetic regulation of replication timing and gene expression.
• To investigate the genomic organization and interspecies conservation of I/SC-associated regulation.

Main Methods:

• Characterization of >100 autosomal loci exhibiting allele-specific epigenetic regulation.
• Analysis of gene expression and replication timing patterns in single-cell derived clones.
• Comparative analysis of syntenic loci in human and mouse genomes.

Main Results:

• Defined I/SCs as ~1 Mb loci containing protein-coding and noncoding genes with stochastic, mitotically stable, allele-specific expression.
• Observed allele-specific replication timing within I/SCs, independent of parental origin or expression status.
• Identified conserved syntenic I/SCs in the mouse genome, indicating conserved regulation between species.
• Demonstrated that I/SC regulation generates extensive cellular mosaicism.

Conclusions:

• I/SCs represent a novel mechanism of allele-restricted epigenetic regulation on autosomes.
• This regulation leads to significant cellular mosaicism impacting numerous dosage-sensitive genes.
• The observed mosaicism is linked to various human diseases, including neurodegenerative and developmental disorders.