PT  - JOURNAL ARTICLE
AU  - Saumya Gupta
AU  - Denis L. Lafontaine
AU  - Sebastien Vigneau
AU  - Svetlana Vinogradova
AU  - Asia Mendelevich
AU  - Kyomi J. Igarashi
AU  - Andrew Bortvin
AU  - Clara F. Alves-Pereira
AU  - Kendell Clement
AU  - Luca Pinello
AU  - Andreas Gnirke
AU  - Henry Long
AU  - Alexander Gusev
AU  - Anwesha Nag
AU  - Alexander A. Gimelbrant
TI  - Mechanism of monoallelic expression and allelic rheostat role of DNA methylation
AID  - 10.1101/2020.02.20.954834
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.20.954834
4099  - http://biorxiv.org/content/early/2020/02/21/2020.02.20.954834.short
4100  - http://biorxiv.org/content/early/2020/02/21/2020.02.20.954834.full
AB  - Thousands of mammalian genes show epigenetically controlled unequal transcription of the parental alleles. Genes subject to autosomal monoallelic expression (MAE) display mitotically stable allelic choice, leading to persistent transcriptional differences between clonal cell lineages. Mechanism of MAE mitotic maintenance is unknown. Using a new screening-by-sequencing strategy, we uncovered a key role for DNA methylation in MAE maintenance. Subset of MAE loci were insensitive to DNA demethylation, suggesting mechanistic heterogeneity of MAE. Genome-wide analyses indicate that MAE is part of a more general mode of gene regulation and reveal a previously unappreciated interplay of genetic and epigenetic control of allele-specific transcription. While cis-acting regulation defines a common underlying state for all cells, DNA methylation plays the role of an allele-specific rheostat and determines multiple regulatory states distinguishing between developmentally equivalent clonal cell lineages. Our findings imply that allele-specific analyses of clonal cell populations can unmask long-term transcriptional responses to drug-driven perturbations.