RT Journal Article
SR Electronic
T1 Mechanism of monoallelic expression and allelic rheostat role of DNA methylation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.20.954834
DO 10.1101/2020.02.20.954834
A1 Saumya Gupta
A1 Denis L. Lafontaine
A1 Sebastien Vigneau
A1 Svetlana Vinogradova
A1 Asia Mendelevich
A1 Kyomi J. Igarashi
A1 Andrew Bortvin
A1 Clara F. Alves-Pereira
A1 Kendell Clement
A1 Luca Pinello
A1 Andreas Gnirke
A1 Henry Long
A1 Alexander Gusev
A1 Anwesha Nag
A1 Alexander A. Gimelbrant
YR 2020
UL http://biorxiv.org/content/early/2020/02/21/2020.02.20.954834.abstract
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.