Stable autosomal monoallelic expression is maintained by multiple mechanisms

2018 ◽  
Vol 07 ◽  
Author(s):  
Alexander A Gimelbrant
Keyword(s):  
Monoallelic Expression

scholarly journals Somatotroph Tumors and the Epigenetic Status of the GNAS Locus

2021 ◽  
Vol 22 (14) ◽  
pp. 7570
Author(s):  
Pauline Romanet ◽  
Justine Galluso ◽  
Peter Kamenicky ◽  
Mirella Hage ◽  
Marily Theodoropoulou ◽  
...  
Keyword(s):  
Genomic Analysis ◽  
Somatostatin Analogues ◽  
Differentially Methylated Region ◽  
Monoallelic Expression ◽  
Lower Sensitivity ◽  
Biallelic Expression ◽  
Expression Levels ◽  
Methylation Index ◽  
Significant Difference ◽  
Gsp Oncogene

Background: Forty percent of somatotroph tumors harbor recurrent activating GNAS mutations, historically called the gsp oncogene. In gsp-negative somatotroph tumors, GNAS expression itself is highly variable; those with GNAS overexpression most resemble phenotypically those carrying the gsp oncogene. GNAS is monoallelically expressed in the normal pituitary due to methylation-based imprinting. We hypothesize that changes in GNAS imprinting of gsp-negative tumors affect GNAS expression levels and tumorigenesis. Methods: We characterized the GNAS locus in two independent somatotroph tumor cohorts: one of 23 tumors previously published (PMID: 31883967) and classified by pan-genomic analysis, and a second with 82 tumors. Results: Multi-omics analysis of the first cohort identified a significant difference between gsp-negative and gsp-positive tumors in the methylation index at the known differentially methylated region (DMR) of the GNAS A/B transcript promoter, which was confirmed in the larger series of 82 tumors. GNAS allelic expression was analyzed using a polymorphic Fok1 cleavage site in 32 heterozygous gsp-negative tumors. GNAS expression was significantly reduced in the 14 tumors with relaxed GNAS imprinting and biallelic expression, compared to 18 tumors with monoallelic expression. Tumors with relaxed GNAS imprinting showed significantly lower SSTR2 and AIP expression levels. Conclusion: Altered A/B DMR methylation was found exclusively in gsp-negative somatotroph tumors. 43% of gsp-negative tumors showed GNAS imprinting relaxation, which correlated with lower GNAS, SSTR2 and AIP expression, indicating lower sensitivity to somatostatin analogues and potentially aggressive behavior.

Monoallelic Expression of Pax5: A Paradigm for the Haploinsufficiency of Mammalian Pax Genes?

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
S.L. Nutt ◽  
M. Busslinger
Keyword(s):  
Human Disease ◽  
Mouse Genome ◽  
Monoallelic Expression ◽  
Wild Type Allele ◽  
Loss Of Function ◽  
Wild Type ◽  
Type Allele ◽  
Pax Genes ◽  
Default State ◽  
Mammalian Genes

AbstractIt is generally assumed that most mammalian genes are transcribed from both alleles. Hence, the diploid state of the genome offers the advantage that a loss-of-function mutation in one allele can be compensated for by the remaining wild-type allele of the same gene. Indeed, the vast majority of human disease syndromes and engineered mutations in the mouse genome are recessive, indicating that recessiveness is the ‘default’ state. However, a minority of genes are semi-dominant, as heterozygous loss-of-function mutation in these genes leads to phenotypic abnormalities. This condition, known as haploinsufficiency, has been described for five of the nine mammalian

An N-Ethyl-N-Nitrosourea Mutagenesis Screen for Epigenetic Mutations in the Mouse

Genetics ◽  
2003 ◽  
Vol 164 (4) ◽  
pp. 1481-1494
Author(s):  
Ivona Percec ◽  
Joanne L Thorvaldsen ◽  
Robert M Plenge ◽  
Christopher J Krapp ◽  
Joseph H Nadeau ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
X Chromosome ◽  
X Inactivation ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Chromosome 5 ◽  
Chromosome 10 ◽  
Mutagenesis Screen ◽  
Distal Chromosome ◽  
Males And Females

Abstract The mammalian epigenetic phenomena of X inactivation and genomic imprinting are incompletely understood. X inactivation equalizes X-linked expression between males and females by silencing genes on one X chromosome during female embryogenesis. Genomic imprinting functionally distinguishes the parental genomes, resulting in parent-specific monoallelic expression of particular genes. N-ethyl-N-nitrosourea (ENU) mutagenesis was used in the mouse to screen for mutations in novel factors involved in X inactivation. Previously, we reported mutant pedigrees identified through this screen that segregate aberrant X-inactivation phenotypes and we mapped the mutation in one pedigree to chromosome 15. We now have mapped two additional mutations to the distal chromosome 5 and the proximal chromosome 10 in a second pedigree and show that each of the mutations is sufficient to induce the mutant phenotype. We further show that the roles of these factors are specific to embryonic X inactivation as neither genomic imprinting of multiple genes nor imprinted X inactivation is perturbed. Finally, we used mice bearing selected X-linked alleles that regulate X chromosome choice to demonstrate that the phenotypes of all three mutations are consistent with models in which the mutations have affected molecules involved specifically in the choice or the initiation of X inactivation.

scholarly journals Probability in transcriptional regulation and its implications for leukocyte differentiation and inducible gene expression

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2323-2328 ◽  
Author(s):  
David A. Hume
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Mammalian Cells ◽  
Cell Lineage ◽  
Monoallelic Expression ◽  
Stem Cell Lineage ◽  
The Stability ◽  
Stochastic Phenomena ◽  
Inducible Genes ◽  
Probabilistic Nature

The phenotype of individual hematopoietic cells, like all other differentiated mammalian cells, is determined by selective transcription of a subset of the genes encoded within the genome. This overview summarizes the recent evidence that transcriptional regulation at the level of individual cells is best described in terms of the regulation of the probability of transcription rather than the rate. In this model, heterogeneous gene expression among populations of cells arises by chance, and the degree of heterogeneity is a function of the stability of the mRNA and protein products of individual genes. The probabilistic nature of transcriptional regulation provides one explanation for stochastic phenomena, such as stem cell lineage commitment, and monoallelic expression of inducible genes, such as lymphokines and cytokines.

scholarly journals ZFP57 dictates allelic expression switch of target imprinted genes

2021 ◽  
Vol 118 (5) ◽  
pp. e2005377118
Author(s):  
Weijun Jiang ◽  
Jiajia Shi ◽  
Jingjie Zhao ◽  
Qiu Wang ◽  
Dan Cong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Mouse Embryos ◽  
The Other ◽  
Allelic Expression ◽  
Monoallelic Expression ◽  
Imprinted Genes ◽  
Parent Of Origin

ZFP57 is a master regulator of genomic imprinting. It has both maternal and zygotic functions that are partially redundant in maintaining DNA methylation at some imprinting control regions (ICRs). In this study, we found that DNA methylation was lost at most known ICRs in Zfp57 mutant embryos. Furthermore, loss of ZFP57 caused loss of parent-of-origin–dependent monoallelic expression of the target imprinted genes. The allelic expression switch occurred in the ZFP57 target imprinted genes upon loss of differential DNA methylation at the ICRs in Zfp57 mutant embryos. Specifically, upon loss of ZFP57, the alleles of the imprinted genes located on the same chromosome with the originally methylated ICR switched their expression to mimic their counterparts on the other chromosome with unmethylated ICR. Consistent with our previous study, ZFP57 could regulate the NOTCH signaling pathway in mouse embryos by impacting allelic expression of a few regulators in the NOTCH pathway. In addition, the imprinted Dlk1 gene that has been implicated in the NOTCH pathway was significantly down-regulated in Zfp57 mutant embryos. Our allelic expression switch models apply to the examined target imprinted genes controlled by either maternally or paternally methylated ICRs. Our results support the view that ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs.

scholarly journals Random and imprinted monoallelic expression

1996 ◽  
Vol 1 (9) ◽  
pp. 795-802 ◽  
Author(s):  
Daisuke Watanabe ◽  
Denise P. Barlow
Keyword(s):  
Monoallelic Expression

Allele-specific in situ hybridization (ASISH) analysis: a novel technique which resolves differential allelic usage of H19 within the same cell lineage during human placental development

Development ◽  
1996 ◽  
Vol 122 (3) ◽  
pp. 839-847 ◽  
Author(s):  
G.I. Adam ◽  
H. Cui ◽  
S.J. Miller ◽  
F. Flam ◽  
R. Ohlsson
Keyword(s):  
In Situ Hybridization ◽  
First Trimester ◽  
Paternal Allele ◽  
Monoallelic Expression ◽  
Hybridization Technique ◽  
Placental Development ◽  
Foetal Development ◽  
Biallelic Expression ◽  
Normal Human

Precursory studies of H19 transcription during human foetal development have demonstrated maternally derived monoallelic expression. Analyses in extra-embryonic tissues, however, have been more equivocal, with discernible levels of expression of the paternal allele of H19 documented in the first trimester placenta. By refining the in situ hybridization technique we have developed an assay to enable the functional imprinting status of H19 to be determined at the cellular level. This assay involves the use of oligonucleotide DNA probes that are able to discriminate between allelic RNA transcripts containing sequence polymorphisms. Biallelic expression of H19 is confined to a subpopulation of cells of the trophoblast lineage, the extravillous cytotrophoblast, while the mesenchymal stroma cells maintain the imprinted pattern of monoallelic expression of H19 throughout placental development. This data demonstrates that the low level of paternal H19 expression previously detected in normal human placenta is not due to a random loss of functional imprinting, but appears to result from a developmentally regulated cell type-specific activation of the paternal allele. In addition, biallelic expression of H19 does not seem to affect the functional imprinting of the insulin-like growth factor II gene, which is monoallelically expressed at relatively high levels in the extra-villous cytotrophoblasts. These results imply that the allelic usage of these two genes in normal human placental development may not be directly analogous to the situation previously documented in the mouse embryo.

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