Random monoallelic expression of genes on autosomes: Parallels with X-chromosome inactivation

Gendrel, Anne-Valérie; Marion‐Poll, Lucile; Katoh, Kimiko; Heard, Edith

doi:10.1016/j.semcdb.2016.04.007

Cited by 47 publications

(83 citation statements)

References 107 publications

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“…There is some evidence that a subset of RME genes are asynchronously replicated and differentially methylated on the two alleles 5,11 . The epi-genetic mechanism by which the cell can break symmetry randomly in development and express one gene monoallelically among a sea of biallelically expressed genes is of great interest 12,13 .…”

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

et al. 2017

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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.

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

et al. 2017

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“…It ensures dosage compensation between XX female and XY male cells (Lyon 1961). Moreover, XCI involves allelic gene regulation resulting in monoallelic expression, a phenomenon shared with several autosomal genes, such as imprinted genes (Gendrel et al 2016). In early mouse embryos, imprinted XCI (iXCI), which always inactivates the paternal X Chromosome, takes place at the four-cell stage.…”

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Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming

et al. 2019

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Induction and reversal of chromatin silencing is critical for successful development, tissue homeostasis, and the derivation of induced pluripotent stem cells (iPSCs). X-Chromosome inactivation (XCI) and reactivation (XCR) in female cells represent chromosome-wide transitions between active and inactive chromatin states. Although XCI has long been studied, providing important insights into gene regulation, the dynamics and mechanisms underlying the reversal of stable chromatin silencing of X-linked genes are much less understood. Here, we use allele-specific transcriptomics to study XCR during mouse iPSC reprogramming in order to elucidate the timing and mechanisms of chromosome-wide reversal of gene silencing. We show that XCR is hierarchical, with subsets of genes reactivating early, late, and very late during reprogramming. Early genes are activated before the onset of late pluripotency genes activation. Early genes are located genomically closer to genes that escape XCI, unlike genes reactivating late. Early genes also show increased pluripotency transcription factor (TF) binding. We also reveal that histone deacetylases (HDACs) restrict XCR in reprogramming intermediates and that the severe hypoacetylation state of the inactive X Chromosome (Xi) persists until late reprogramming stages. Altogether, these results reveal the timing of transcriptional activation of monoallelically repressed genes during iPSC reprogramming, and suggest that allelic activation involves the combined action of chromatin topology, pluripotency TFs, and chromatin regulators. These findings are important for our understanding of gene silencing, maintenance of cell identity, reprogramming, and disease.

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“…Inter-individual penetrance of the phenotype was observed in MFDA-affected individuals like in Ednra Y129F/ + and Ednra Y129F/Y129F mice. Incomplete penetrance of the phenotype in autosomal dominant diseases may depend on genetic and environmental factors such as modifier genes, DNA sequence polymorphisms in regulatory elements, and random monoallelic expression of autosomal genes, where genes can be stably expressed, from either of the parental alleles (Cooper et al 2013; Gendrel et al 2016). …”

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Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

et al. 2016

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Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra Y129F mice within the German Mouse Clinic. Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra Y129F mice exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)–endothelin receptor type A (EDNRA) signaling. Above all, Ednra Y129F mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-016-9664-5) contains supplementary material, which is available to authorized users.

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Random monoallelic expression of genes on autosomes: Parallels with X-chromosome inactivation

Cited by 47 publications

References 107 publications

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

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

Dynamic reversal of random X-Chromosome inactivation during iPSC reprogramming

Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

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