Allele-specific ATAC-seq across 16 neural progenitor cell clones

The two copies of a gene are canonically believed to be indistinguishable to the cell and are expressed in the same spatiotemporal manner in the absence of a loss-of-function mutation.  The mechanisms by which cells break this symmetry and express a gene from only one of the two alleles of the diploid genome are of great interest.  Monoallelic gene expression on the X-chromosome, at imprinted genes, and at olfactory receptor genes has been studied in detail and involves combinations of non-coding RNAs, DNA methylation, and histone modifications.  Recently, random monoallelic gene expression (RME), in which a gene can be expressed from either or both alleles in a clonal manner, has been described across many cell types and disease-relevant genes. However little is known about how RME is established and regulated. Here we develop allele-specific ATAC-seq, a rapid and sensitive method for profiling active regulatory DNA allelically and genome-wide, and find that monoallelic chromatin accessibility is extensive, developmentally regulated, and epigenetically inherited. In clonal hybrid F1 murine neural progenitor cells, we find over 1800 monoallelically-accessible DNA elements across autosomes.  Randomly monoallelic regulatory elements tend to be promoter-proximal and located at RME genes identified by RNA-seq.  Following differentiation, they are highly stable across passages and bookmarked during mitosis. Most RME genes have monoallelic promoters, but surprisingly, the nearby enhancer landscape around RME genes is biallelic.  This suggests that RME genes are regulated at the chromatin, not post-transcriptional level, and that highly localized promoter accessibility is the gatekeeper within a permissive regulatory landscape dictating monoallelic vs. biallelic expression.  These randomly monoallelic promoters are biallelically accessible in a previous developmental state, indicating that one allele is randomly shut down during NPC specification. Furthermore, the distribution of active alleles for a subset of these randomly monoallelic regulatory elements across clones deviates from a binomial distribution, indicating a highly regulated, non-stochastic mechanism of establishment. Overall design: ATAC-seq was performed in mESCs and mNPCs. Libraries(2 replicates per line) were sequenced on an Illumina NextSeq (2x75bp) and data was analyzed allele-specifically. Please note that [1] the .bed contains peaks for all NPCs. [2] Peaks for 'ESC_XX1 ATAC-seq' were previously published and also added to GEO (GSM1828645; duplicated sample record for the convenient retrieval of the complete raw data from SRA) [3] The ESC_XY2 raw sequencing reads was included in the analyses. The peaks from this sample, however are not used and therefore not provided [4] Additional bigwigs will be provided separately as a hub with publication.