Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain

The maternal and paternal genomes play different roles in mammalian brains as a result of genomic imprinting, an epigenetic regulation leading to differential expression of the parental alleles of some genes. Here we investigate genomic imprinting in the cerebellum using a newly developed Bayesian statistical model that provides unprecedented transcript-level resolution. We uncover 160 imprinted transcripts, including 41 novel and independently validated imprinted genes. Strikingly, many genes exhibit parentally biased—rather than monoallelic—expression, with different magnitudes according to age, organ, and brain region. Developmental changes in parental bias and overall gene expression are strongly correlated, suggesting combined roles in regulating gene dosage. Finally, brain-specific deletion of the paternal, but not maternal, allele of the paternally-biased Bcl-x, (Bcl2l1) results in loss of specific neuron types, supporting the functional significance of parental biases. These findings reveal the remarkable complexity of genomic imprinting, with important implications for understanding the normal and diseased brain.

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Loss of genomic imprinting in Drosophila clones

Genome ◽

10.1139/g06-042 ◽

2006 ◽

Vol 49 (8) ◽

pp. 1043-1046 ◽

Cited By ~ 3

Author(s):

Andrew J Haigh ◽

Vett K Lloyd

Keyword(s):

Drosophila Melanogaster ◽

Genomic Imprinting ◽

X Chromosome ◽

Chromatin Structure ◽

Nuclear Transfer ◽

Paternal Allele ◽

Monoallelic Expression ◽

C Elegans ◽

Human Cancers ◽

Parent Of Origin

Genomic imprinting is a process that genetically distinguishes maternal and paternal genomes, and can result in parent-of-origin-dependent monoallelic expression of a gene that is dependent on the parent of origin. As such, an otherwise functional maternally inherited allele may be silenced so that the gene is expressed exclusively from the paternal allele, or vice versa. Once thought to be restricted to mammals, genomic imprinting has been documented in angiosperm plants (J.L. Kermicle. 1970. Genetics, 66: 6985), zebrafish (C.C. Martin and R. McGowan. 1995. Genet. Res. 65: 2128), insects, and C. elegans (C.J. Bean, C.E. Schaner, and W.G. Kelly. 2004. Nat. Genet. 36: 100105.). In each case, it appears to rely on differential chromatin structure. Aberrant imprinting has been implicated in various human cancers and has been detected in a number of cloned mammals, potentially limiting the usefulness of somatic nuclear transfer. Here we show that genomic imprinting associated with a mini-X chromosome is lost in Drosophila melanogaster clones.Key words: cloning, Drosophila, genomic imprinting, nuclear transfer.

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Quantifying Genomic Imprinting at Tissue and Cell Resolution in the Brain

Epigenomes ◽

10.3390/epigenomes4030021 ◽

2020 ◽

Vol 4 (3) ◽

pp. 21

Author(s):

Annie Varrault ◽

Emeric Dubois ◽

Anne Le Digarcher ◽

Tristan Bouschet

Keyword(s):

Single Cell ◽

Rna Sequencing ◽

Genomic Imprinting ◽

Molecular Probes ◽

Brain Diseases ◽

Imprinted Genes ◽

F1 Hybrid ◽

Imprinted Gene ◽

Parent Of Origin ◽

The Brain

Imprinted genes are a group of ~150 genes that are preferentially expressed from one parental allele owing to epigenetic marks asymmetrically distributed on inherited maternal and paternal chromosomes. Altered imprinted gene expression causes human brain disorders such as Prader-Willi and Angelman syndromes and additional rare brain diseases. Research data principally obtained from the mouse model revealed how imprinted genes act in the normal and pathological brain. However, a better understanding of imprinted gene functions calls for building detailed maps of their parent-of-origin-dependent expression and of associated epigenetic signatures. Here we review current methods for quantifying genomic imprinting at tissue and cell resolutions, with a special emphasis on methods to detect parent-of-origin dependent expression and their applications to the brain. We first focus on bulk RNA-sequencing, the main method to detect parent-of-origin-dependent expression transcriptome-wide. We discuss the benefits and caveats of bulk RNA-sequencing and provide a guideline to use it on F1 hybrid mice. We then review methods for detecting parent-of-origin-dependent expression at cell resolution, including single-cell RNA-seq, genetic reporters, and molecular probes. Finally, we provide an overview of single-cell epigenomics technologies that profile additional features of genomic imprinting, including DNA methylation, histone modifications and chromatin conformation and their combination into sc-multimodal omics approaches, which are expected to yield important insights into genomic imprinting in individual brain cells.

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UNIPARENTAL DISOMY: MECHANISMS AND CLINICAL CONSEQUENCES

Fetal and Maternal Medicine Review ◽

10.1017/s0965539503001062 ◽

2003 ◽

Vol 14 (2) ◽

pp. 155-175 ◽

Cited By ~ 4

Author(s):

LISA G SHAFFER

Keyword(s):

Genomic Imprinting ◽

Normal State ◽

Diploid Number ◽

Uniparental Disomy ◽

Monoallelic Expression ◽

Clinical Consequences ◽

Epigenetic Phenomenon ◽

Parent Of Origin

During gametogenesis in mammals, half of the parental chromosomes segregate to each gamete. Upon fertilization of two haploid gametes, the diploid number is restored (Figure 1A). Nondisjunction, malsegregation of the chromosomes during gametogenesis, can give rise to chromosomally unbalanced offspring (trisomies and monosomies) (Figure 1B). Genomic imprinting is an epigenetic phenomenon in which the activity of a gene is reversibly modified depending on the parent of origin. This leads to unequal, monoallelic expression of the maternal and paternal alleles of a diploid locus (Figure 1C). Thus, the normal state of an imprinted locus is an “imbalance”, not of chromosomes, but of the functional genetic content.

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

Genetics ◽

10.1093/genetics/164.4.1481 ◽

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.

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Information-based analysis of the coupling between brain and heart reactions to olfactory stimulation

Technology and Health Care ◽

10.3233/thc-213136 ◽

2021 ◽

pp. 1-11

Author(s):

Najmeh Pakniyat ◽

Mohammad Hossein Babini ◽

Vladimir V. Kulish ◽

Hamidreza Namazi

Keyword(s):

Time Series ◽

Biomedical Science ◽

Strongly Correlated ◽

Eeg Signals ◽

Ecg Signals ◽

Olfactory Stimuli ◽

Electrocardiogram Ecg ◽

First Time ◽

Electroencephalogram Eeg ◽

The Brain

BACKGROUND: Analysis of the heart activity is one of the important areas of research in biomedical science and engineering. For this purpose, scientists analyze the activity of the heart in various conditions. Since the brain controls the heart’s activity, a relationship should exist among their activities. OBJECTIVE: In this research, for the first time the coupling between heart and brain activities was analyzed by information-based analysis. METHODS: Considering Shannon entropy as the indicator of the information of a system, we recorded electroencephalogram (EEG) and electrocardiogram (ECG) signals of 13 participants (7 M, 6 F, 18–22 years old) in different external stimulations (using pineapple, banana, vanilla, and lemon flavors as olfactory stimuli) and evaluated how the information of EEG signals and R-R time series (as heart rate variability (HRV)) are linked. RESULTS: The results indicate that the changes in the information of the R-R time series and EEG signals are strongly correlated (ρ=-0.9566). CONCLUSION: We conclude that heart and brain activities are related.

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ZFP57 dictates allelic expression switch of target imprinted genes

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2005377118 ◽

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.

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Genomic imprinting and parent-of-origin effects on complex traits

Nature Reviews Genetics ◽

10.1038/nrg3543 ◽

2013 ◽

Vol 14 (9) ◽

pp. 609-617 ◽

Cited By ~ 128

Author(s):

Heather A. Lawson ◽

James M. Cheverud ◽

Jason B. Wolf

Keyword(s):

Genomic Imprinting ◽

Complex Traits ◽

Parent Of Origin ◽

Origin Effects

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DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812847115 ◽

2018 ◽

Vol 115 (42) ◽

pp. E9962-E9970 ◽

Cited By ~ 15

Author(s):

Haifeng Zhu ◽

Wenxiang Xie ◽

Dachao Xu ◽

Daisuke Miki ◽

Kai Tang ◽

...

Keyword(s):

Gene Expression ◽

Seed Dormancy ◽

Genomic Imprinting ◽

Dna Demethylation ◽

Paternal Allele ◽

Maternal Allele ◽

Imprinted Gene ◽

Differential Gene ◽

Parent Of Origin ◽

Dna Demethylase

Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.

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Information-based Analysis of the Coupling between Dynamic Visual Stimuli, Eye Movements, and Brain Signals

Fluctuation and Noise Letters ◽

10.1142/s0219477521500486 ◽

2021 ◽

pp. 2150048

Author(s):

Hamidreza Namazi ◽

Avinash Menon ◽

Ondrej Krejcar

Keyword(s):

Eye Movements ◽

Moving Objects ◽

Brain Activity ◽

Visual Stimuli ◽

Strongly Correlated ◽

Eeg Signals ◽

Vision Science ◽

Brain Signals ◽

Information Contents ◽

The Brain

Our eyes are always in search of exploring our surrounding environment. The brain controls our eyes’ activities through the nervous system. Hence, analyzing the correlation between the activities of the eyes and brain is an important area of research in vision science. This paper evaluates the coupling between the reactions of the eyes and the brain in response to different moving visual stimuli. Since both eye movements and EEG signals (as the indicator of brain activity) contain information, we employed Shannon entropy to decode the coupling between them. Ten subjects looked at four moving objects (dynamic visual stimuli) with different information contents while we recorded their EEG signals and eye movements. The results demonstrated that the changes in the information contents of eye movements and EEG signals are strongly correlated ([Formula: see text]), which indicates a strong correlation between brain and eye activities. This analysis could be extended to evaluate the correlation between the activities of other organs versus the brain.

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The discovery and importance of genomic imprinting

eLife ◽

10.7554/elife.42368 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Anne C Ferguson-Smith ◽

Deborah Bourchis

Keyword(s):

Gene Expression ◽

Genomic Imprinting ◽

Genetic Disorders ◽

Epigenetic Inheritance ◽

Specific Gene ◽

Specific Gene Expression ◽

Epigenetic Control ◽

International Award ◽

Parent Of Origin ◽

Shed Light

The discovery of genomic imprinting by Davor Solter, Azim Surani and co-workers in the mid-1980s has provided a foundation for the study of epigenetic inheritance and the epigenetic control of gene activity and repression, especially during development. It also has shed light on a range of diseases, including both rare genetic disorders and common diseases. This article is being published to celebrate Solter and Surani receiving a 2018 Canada Gairdner International Award "for the discovery of mammalian genomic imprinting that causes parent-of-origin specific gene expression and its consequences for development and disease".

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