Landscape of monoallelic DNA accessibility in mouse embryonic stem cells and neural progenitor cells

• DOI: 10.1038/ng.3769
• Publication Date: 2017-01-23T11:53:46Z
• Authors: Jin Xu; Ava C Carter; Anne-Valerie Gendrel; Mikael Attia; Joshua Loftus; William J Greenleaf; Robert Tibshirani; Edith Heard; Howard Y Chang
• Keywords: Male; 0303 health sciences; Stem Cells; High-Throughput Nucleotide Sequencing; Cell Differentiation; Mouse Embryonic Stem Cells; DNA; Regulatory Sequences, Nucleic Acid; Chromatin; Cell Line; Mice; 03 medical and health sciences; Neural Stem Cells; Animals; Female; Promoter Regions, Genetic; Alleles

We developed an allele-specific assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) to genotype and profile active regulatory DNA across the genome. Using a mouse hybrid F1 system, we found that monoallelic DNA accessibility across autosomes was pervasive, developmentally programmed and composed of several patterns. Genetically determined accessibility was enriched at distal enhancers, but random monoallelically accessible (RAMA) elements were enriched at promoters and may act as gatekeepers of monoallelic mRNA expression. Allelic choice at RAMA elements was stable across cell generations and bookmarked through mitosis. RAMA elements in neural progenitor cells were biallelically accessible in embryonic stem cells but premarked with bivalent histone modifications; one allele was silenced during differentiation. Quantitative analysis indicated that allelic choice at the majority of RAMA elements is consistent with a stochastic process; however, up to 30% of RAMA elements may deviate from the expected pattern, suggesting a regulated or counting mechanism.