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1.
PLoS Genet ; 16(10): e1009069, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33057429

RESUMO

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.


Assuntos
Fator de Crescimento Insulin-Like II/genética , Mesoderma/crescimento & desenvolvimento , Pâncreas/crescimento & desenvolvimento , Comunicação Parácrina/genética , Células Acinares/metabolismo , Células Acinares/patologia , Aminoácidos/genética , Animais , Linhagem da Célula/genética , Cromo , Metilação de DNA/genética , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica no Desenvolvimento/genética , Impressão Genômica/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Camundongos , Ácidos Nicotínicos/genética , Pâncreas/citologia , Pâncreas/metabolismo , Gravidez , RNA Longo não Codificante/genética
2.
Nucleic Acids Res ; 48(21): e123, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33074315

RESUMO

The recently developed Hi-C technique has been widely applied to map genome-wide chromatin interactions. However, current methods for analyzing diploid Hi-C data cannot fully distinguish between homologous chromosomes. Consequently, the existing diploid Hi-C analyses are based on sparse and inaccurate allele-specific contact matrices, which might lead to incorrect modeling of diploid genome architecture. Here we present ASHIC, a hierarchical Bayesian framework to model allele-specific chromatin organizations in diploid genomes. We developed two models under the Bayesian framework: the Poisson-multinomial (ASHIC-PM) model and the zero-inflated Poisson-multinomial (ASHIC-ZIPM) model. The proposed ASHIC methods impute allele-specific contact maps from diploid Hi-C data and simultaneously infer allelic 3D structures. Through simulation studies, we demonstrated that ASHIC methods outperformed existing approaches, especially under low coverage and low SNP density conditions. Additionally, in the analyses of diploid Hi-C datasets in mouse and human, our ASHIC-ZIPM method produced fine-resolution diploid chromatin maps and 3D structures and provided insights into the allelic chromatin organizations and functions. To summarize, our work provides a statistically rigorous framework for investigating fine-scale allele-specific chromatin conformations. The ASHIC software is publicly available at https://github.com/wmalab/ASHIC.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/ultraestrutura , Mapeamento Cromossômico/estatística & dados numéricos , Software , Alelos , Animais , Teorema de Bayes , Cromatina/metabolismo , Mapeamento Cromossômico/métodos , Simulação por Computador , Diploide , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Impressão Genômica , Histonas/genética , Histonas/metabolismo , Humanos , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Internet , Camundongos , Polimorfismo de Nucleotídeo Único
3.
Biochim Biophys Acta Gene Regul Mech ; 1863(11): 194643, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33035707

RESUMO

H19 is a maternally-expressed imprinted gene that encodes long non-coding RNA. Chromatin immunoprecipitation (ChIP)-sequencing analyses of human adipose-derived stem cells (hADSCs) showed that hypoxia induced trimethylation of 4th lysine residue of histone 3 (H3K4me3) in the H19 gene, among the 40 known human imprinted genes, to the greatest extent. We investigated whether hypoxia changed the DNA and histone methylation levels of the imprinted H19 gene in an allele-specific (AS) manner. Using AS primer sets for the human H19 gene, we conducted ChIP-quantitative polymerase chain reaction, which revealed that hypoxia increased the active histone marks, H3K4me3 and H3K9/14Ac, in one allele (named B allele) but not in the other allele (named A allele). In contrast, hypoxia did not change the H3K9me3 levels in either allele. Hypoxia-inducible factor 1 (HIF-1) directly bound to the H19 promoter only in the B allele. HIF-1α knock-down prevented the increase in the active histone modification and mRNA expression of the B allele under hypoxia, indicating that HIF-1α caused AS changes in the histone modification of the H19 gene. Long-term hypoxia did not change the AS DNA methylation throughout the cell cycle. Thus, hypoxia changed the histone modification of the active allele in an HIF-1α-dependent manner, without changing the imprinted status of the H19 gene.


Assuntos
Alelos , Regulação da Expressão Gênica , Impressão Genômica , Histonas/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , RNA Longo não Codificante/genética , Sequência de Bases , Metilação de DNA , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metilação , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Processamento de Proteína Pós-Traducional , Análise de Sequência de DNA
4.
Nucleic Acids Res ; 48(20): 11394-11407, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-33053156

RESUMO

Genomic imprinting is an epigenetic process regulated by germline-derived DNA methylation that is resistant to embryonic reprogramming, resulting in parental origin-specific monoallelic gene expression. A subset of individuals affected by imprinting disorders (IDs) displays multi-locus imprinting disturbances (MLID), which may result from aberrant establishment of imprinted differentially methylated regions (DMRs) in gametes or their maintenance in early embryogenesis. Here we investigated the extent of MLID in a family harbouring a ZFP57 truncating variant and characterize the interactions between human ZFP57 and the KAP1 co-repressor complex. By ectopically targeting ZFP57 to reprogrammed loci in mouse embryos using a dCas9 approach, we confirm that ZFP57 recruitment is sufficient to protect oocyte-derived methylation from reprogramming. Expression profiling in human pre-implantation embryos and oocytes reveals that unlike in mice, ZFP57 is only expressed following embryonic-genome activation, implying that other KRAB-zinc finger proteins (KZNFs) recruit KAP1 prior to blastocyst formation. Furthermore, we uncover ZNF202 and ZNF445 as additional KZNFs likely to recruit KAP1 to imprinted loci during reprogramming in the absence of ZFP57. Together, these data confirm the perplexing link between KZFPs and imprint maintenance and highlight the differences between mouse and humans in this respect.


Assuntos
Metilação de DNA , Embrião de Mamíferos/metabolismo , Impressão Genômica , Células Germinativas/metabolismo , Oócitos/metabolismo , Proteínas Repressoras/metabolismo , Síndrome de Beckwith-Wiedemann/metabolismo , Estudos de Coortes , DNA (Citosina-5-)-Metiltransferases/metabolismo , Humanos , Análise em Microsséries , Mutação , Linhagem , Pseudo-Hipoparatireoidismo/metabolismo , RNA-Seq , Proteínas Repressoras/genética , Irmãos , Transcriptoma , Proteína 28 com Motivo Tripartido
5.
Mol Immunol ; 127: 112-123, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961421

RESUMO

A highly diverse repertoire of T cell antigen receptors (TCR) is created in the thymus by recombination of gene segments and the insertion or deletion of nucleotides at the junctions. Using next-generation TCR sequencing we define here the features of recombination and selection in the human TCRα and TCRß locus, and show that a strikingly high proportion of the repertoire is shared by unrelated individuals. The thymic TCRα nucleotide repertoire was more diverse than TCRß, with 4.1 × 106 vs. 0.81 × 106 unique clonotypes, and contained nonproductive clonotypes at a higher frequency (69.2% vs. 21.2%). The convergence of distinct nucleotide clonotypes to the same amino acid sequences was higher in TCRα than in TCRß repertoire (1.45 vs. 1.06 nucleotide sequences per amino acid sequence in thymus). The gene segment usage was biased, and generally all individuals favored the same genes in both TCRα and TCRß loci. Despite the high diversity, a large fraction of the repertoire was found in more than one donor. The shared fraction was bigger in TCRα than TCRß repertoire, and more common in in-frame sequences than in nonproductive sequences. Thus, both biases in rearrangement and thymic selection are likely to contribute to the generation of shared repertoire in humans.


Assuntos
Impressão Genômica , Linfócitos T/imunologia , Timo/citologia , Sequência de Bases , Células Clonais , Regiões Determinantes de Complementaridade/genética , Feminino , Variação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutagênese Insercional , Probabilidade , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Recombinação Genética/genética
6.
PLoS Genet ; 16(9): e1008916, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32877400

RESUMO

Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was expressed predominantly (~70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studying Trappc9 null mice we discovered that homozygous mutant mice showed a reduction in brain size, exploratory activity and social memory, as well as a marked increase in body weight. A role for Trappc9 in energy balance was further supported by increased ad libitum food intake in a child with TRAPPC9 deficiency. Strikingly, heterozygous mice lacking the maternal allele (70% reduced expression) had pathology similar to homozygous mutants, whereas mice lacking the paternal allele (30% reduction) were phenotypically normal. Taken together, we conclude that Trappc9 deficient mice recapitulate key pathological features of TRAPPC9 mutations in humans and identify a role for Trappc9 and its imprinting in controlling brain development and metabolism.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Microcefalia/genética , Obesidade/genética , Animais , Criança , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Impressão Genômica , Heterozigoto , Homozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Herança Materna , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcefalia/metabolismo , Mutação , Obesidade/metabolismo , Fenótipo
7.
Neuron ; 107(6): 994-996, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32971001

RESUMO

In this issue, Laukoter et al., 2020 report that parent-of-origin-dependent expression is homogeneous across distinct cortical cell types and within individual populations. Conversely, they observe preferential sensitivity of astrocytes to altered doses of imprinted loci.


Assuntos
Córtex Cerebral , Impressão Genômica , Alelos , Expressão Gênica , Humanos , Pais
8.
Nat Commun ; 11(1): 4593, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929070

RESUMO

Gene-targeted animal models that are generated by injecting Cas9 and sgRNAs into zygotes are often accompanied by undesired double-strand break (DSB)-induced byproducts and random biallelic targeting due to uncontrollable Cas9 targeting activity. Here, we establish a parental allele-specific gene-targeting (Past-CRISPR) method, based on the detailed observation that pronuclear transfer-mediated cytoplasmic dilution can effectively terminate Cas9 activity. We apply this method in embryos to efficiently target the given parental alleles of a gene of interest and observed little genomic mosaicism because of the spatiotemporal control of Cas9 activity. This method allows us to rapidly explore the function of individual parent-of-origin effects and to construct animal models with a single genomic change. More importantly, Past-CRISPR could also be used for therapeutic applications or disease model construction.


Assuntos
Alelos , Sistemas CRISPR-Cas/genética , Núcleo Celular/genética , Edição de Genes , Terapia de Substituição Mitocondrial , Animais , Sequência de Bases , Modelos Animais de Doenças , Nanismo/genética , Perda do Embrião/genética , Feminino , Marcação de Genes , Genes Dominantes , Impressão Genômica , Heterozigoto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Reprodutibilidade dos Testes , Fatores de Tempo
9.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(8): 875-878, 2020 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-32761599

RESUMO

OBJECTIVE: To discuss the advantages and technical limitations of various molecular genetic techniques in the diagnosis of two infants featuring all-round developmental retardation. METHODS: The two patients were initially screened by using chromosomal microarray analysis (CMA). For patient 1, his parents were also subjected to CMA analysis, and the data was analyzed by using ChAS and UPD-tool software. For patient 2, methylation-specific PCR (MS-PCR) was carried out. RESULTS: Patient 1 was diagnosed with maternal uniparental disomy (UPD) type Prader-Willi syndrome (PWS) by CMA and UPD-tool family analysis. His chromosomes 15 were of maternal UPD with homology/heterology. Patient 2 was diagnosed with deletion type PWS by combined CMA and MS-PCR. CONCLUSION: Correct selection of laboratory methods based on the advantages and limitations of various molecular techniques can help with diagnosis of genomic imprinting disorders and enable better treatment and prognosis through early intervention.


Assuntos
Testes Genéticos/métodos , Síndrome de Prader-Willi , Cromossomos Humanos Par 15/genética , Impressão Genômica , Humanos , Lactente , Masculino , Análise em Microsséries , Reação em Cadeia da Polimerase , Síndrome de Prader-Willi/diagnóstico , Síndrome de Prader-Willi/genética , Dissomia Uniparental/diagnóstico , Dissomia Uniparental/genética
11.
PLoS Genet ; 16(8): e1008930, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32760061

RESUMO

Genomic imprinting is a parent-of-origin dependent phenomenon that restricts transcription to predominantly one parental allele. Since the discovery of the first long noncoding RNA (lncRNA), which notably was an imprinted lncRNA, a body of knowledge has demonstrated pivotal roles for imprinted lncRNAs in regulating parental-specific expression of neighboring imprinted genes. In this Review, we will discuss the multiple functionalities attributed to lncRNAs and how they regulate imprinted gene expression. We also raise unresolved questions about imprinted lncRNA function, which may lead to new avenues of investigation. This Review is dedicated to the memory of Denise Barlow, a giant in the field of genomic imprinting and functional lncRNAs. With her passion for understanding the inner workings of science, her indominable spirit and her consummate curiosity, Denise blazed a path of scientific investigation that made many seminal contributions to genomic imprinting and the wider field of epigenetic regulation, in addition to inspiring future generations of scientists.


Assuntos
Impressão Genômica , RNA Longo não Codificante/genética , Animais , Humanos , RNA Longo não Codificante/metabolismo
12.
Eur J Endocrinol ; 183(4): R107-R117, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32698138

RESUMO

Pubertal timing is regulated by the complex interplay of genetic, environmental, nutritional and epigenetic factors. Criteria for determining normal pubertal timing, and thus the definition of precocious puberty, have evolved based on published population studies. The significance of the genetic influence on pubertal timing is supported by familial pubertal timing and twin studies. In contrast to the many monogenic causes associated with hypogonadotropic hypogonadism, only four monogenic causes of central precocious puberty (CPP) have been described. Loss-of-function mutations in Makorin Ring Finger Protein 3(MKRN3), a maternally imprinted gene on chromosome 15 within the Prader-Willi syndrome locus, are the most common identified genetic cause of CPP. More recently, several mutations in a second maternally imprinted gene, Delta-like noncanonical Notch ligand 1 (DLK1), have also been associated with CPP. Polymorphisms in both genes have also been associated with the age of menarche in genome-wide association studies. Mutations in the genes encoding kisspeptin (KISS1) and its receptor (KISS1R), potent activators of GnRH secretion, have also been described in association with CPP, but remain rare monogenic causes. CPP has both short- and long-term health implications for children, highlighting the importance of understanding the mechanisms contributing to early puberty. Additionally, given the role of mutations in the imprinted genes MKRN3 and DLK1 in pubertal timing, other imprinted candidate genes should be considered for a role in puberty initiation.


Assuntos
Impressão Genômica/fisiologia , Puberdade Precoce/genética , Adolescente , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Kisspeptinas/genética , Masculino , Mutação , Puberdade/genética , Puberdade Precoce/epidemiologia , Receptores de Kisspeptina-1/genética
13.
Nucleic Acids Res ; 48(15): 8431-8444, 2020 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-32667642

RESUMO

Genome-wide passive DNA demethylation in cleavage-stage mouse embryos is related to the cytoplasmic localization of the maintenance methyltransferase DNMT1. However, recent studies provided evidences of the nuclear localization of DNMT1 and its contribution to the maintenance of methylation levels of imprinted regions and other genomic loci in early embryos. Using the DNA adenine methylase identification method, we identified Dnmt1-binding regions in four- and eight-cell embryos. The unbiased distribution of Dnmt1 peaks in the genic regions (promoters and CpG islands) as well as the absence of a correlation between the Dnmt1 peaks and the expression levels of the peak-associated genes refutes the active participation of Dnmt1 in the transcriptional regulation of genes in the early developmental period. Instead, Dnmt1 was found to associate with genomic retroelements in a greatly biased fashion, particularly with the LINE1 (long interspersed nuclear elements) and ERVK (endogenous retrovirus type K) sequences. Transcriptomic analysis revealed that the transcripts of the Dnmt1-enriched retroelements were overrepresented in Dnmt1 knockdown embryos. Finally, methyl-CpG-binding domain sequencing proved that the Dnmt1-enriched retroelements, which were densely methylated in wild-type embryos, became demethylated in the Dnmt1-depleted embryos. Our results indicate that Dnmt1 is involved in the repression of retroelements through DNA methylation in early mouse development.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/genética , Metilação de DNA/genética , Desenvolvimento Embrionário/genética , Genômica , Retroelementos/genética , Animais , Ilhas de CpG/genética , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos , Perfilação da Expressão Gênica , Genoma/genética , Impressão Genômica/genética , Camundongos , Fatores de Transcrição/genética
14.
Neuron ; 107(6): 1160-1179.e9, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32707083

RESUMO

In mammalian genomes, a subset of genes is regulated by genomic imprinting, resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development, but prevalence and functional impact in individual cells is unclear. Here, we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental chromosome disomy (UPD) containing two copies of either the maternal or the paternal chromosome; hence, imprinted genes will be 2-fold overexpressed or not expressed. By genetic labeling of UPD, we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single-cell resolution. We discovered an unexpected degree of cell-type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally, our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell-type diversity.


Assuntos
Córtex Cerebral/metabolismo , Impressão Genômica , Transcriptoma , Dissomia Uniparental , Animais , Astrócitos/classificação , Astrócitos/metabolismo , Córtex Cerebral/citologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA-Seq , Análise de Célula Única
15.
Sci Rep ; 10(1): 11562, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665606

RESUMO

Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10-24) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.


Assuntos
Artrite Reumatoide/genética , Variação Biológica da População/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Adolescente , Adulto , Idoso , Artrite Reumatoide/patologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/patologia , Epigênese Genética/genética , Feminino , Genética Populacional , Impressão Genômica/genética , Genótipo , Humanos , Lactente , Masculino , Herança Materna/genética , Pessoa de Meia-Idade , Linhagem , Adulto Jovem
16.
Nucleic Acids Res ; 48(16): e92, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32621604

RESUMO

Genomic imprinting is an epigenetic phenomenon leading to parental allele-specific expression. Dosage of imprinted genes is crucial for normal development and its dysregulation accounts for several human disorders. This unusual expression pattern is mostly dictated by differences in DNA methylation between parental alleles at specific regulatory elements known as imprinting control regions (ICRs). Although several approaches can be used for methylation inspection, we lack an easy and cost-effective method to simultaneously measure DNA methylation at multiple imprinted regions. Here, we present IMPLICON, a high-throughput method measuring DNA methylation levels at imprinted regions with base-pair resolution and over 1000-fold coverage. We adapted amplicon bisulfite-sequencing protocols to design IMPLICON for ICRs in adult tissues of inbred mice, validating it in hybrid mice from reciprocal crosses for which we could discriminate methylation profiles in the two parental alleles. Lastly, we developed a human version of IMPLICON and detected imprinting errors in embryonic and induced pluripotent stem cells. We also provide rules and guidelines to adapt this method for investigating the DNA methylation landscape of any set of genomic regions. In summary, IMPLICON is a rapid, cost-effective and scalable method, which could become the gold standard in both imprinting research and diagnostics.


Assuntos
Ilhas de CpG , Metilação de DNA , Impressão Genômica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Animais , Células Cultivadas , Feminino , Fibroblastos , Células-Tronco Embrionárias Humanas , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
BMC Genomics ; 21(1): 378, 2020 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-32475352

RESUMO

BACKGROUND: Genomic imprinting is a process thereby a subset of genes is expressed in a parent-of-origin specific manner. This evolutionary novelty is restricted to mammals and controlled by genomic DNA segments known as Imprinting Control Regions (ICRs) and germline Differentially Methylated Regions (gDMRs). Previously, I showed that in the mouse genome, the fully characterized ICRs/gDMRs often includes clusters of 2 or more of a set of composite-DNA-elements known as ZFBS-morph overlaps. RESULTS: Because of the importance of the ICRs to regulating parent-of-origin specific gene expression, I developed a genome-wide strategy for predicting their positions in the human genome. My strategy consists of creating plots to display the density of ZFBS-morph overlaps along the entire chromosomal DNA sequences. In initial evaluations, I found that peaks in these plots pinpointed several of the known ICRs/gDMRs along the DNA in chromosomal bands. I deduced that in density-plots, robust peaks corresponded to actual or candidate ICRs in the DNA. By locating the genes in the vicinity of candidate ICRs, I could discover potential imprinting genes. Additionally, my assessments revealed a connection between several of the potential imprinted genes and human developmental anomalies. Examples include Leber congenital amaurosis 11, Coffin-Siris syndrome, progressive myoclonic epilepsy-10, microcephalic osteodysplastic primordial dwarfism type II, and microphthalmia, cleft lip and palate, and agenesis of the corpus callosum. CONCLUSION: With plots displaying the density of ZFBS-morph overlaps, researchers could locate candidate ICRs and imprinted genes. Since the datafiles are available for download and display at the UCSC genome browser, it is possible to examine the plots in the context of Single nucleotide polymorphisms (SNPs) to design experiments to discover novel ICRs and imprinted genes in the human genome.


Assuntos
Genoma Humano/genética , Impressão Genômica , Genômica , Humanos
18.
Orv Hetil ; 161(25): 1028-1034, 2020 06.
Artigo em Húngaro | MEDLINE | ID: mdl-32516120

RESUMO

During conception (fusion of maternal and paternal germ cells) a new entity is formed, which has individual structure and functions. From its gene-pool (genome) epigenetic regulation selects those genes which are durably or acutely working, supplying a theoretically lifelong program. However, this program could be changed spontaneously or artificially, and there are life periods when the spontaneous changes are especially frequent and the sensitivity to physiological or artificial (man-made) factors is high. The basic sensitive (most vulnerable) period is the perinatal one, when the program agglomerated (and this is manifested in the faulty hormonal imprinting and DOHaD theories: perinatal adverse effects can cause diseases in adults), however, later periods are also sensitive. Such rather sensitive periods are the puberty and periadolescence as well as weaning, nevertheless, in any periods of life, cells or cell groups could be epigenetically imprinted, if the cells are in the state of differentiation, independent of the age or developmental state of the complete organism. Earlier mainly natural molecules (products of volcanic eruptions or phytoestrogens, mykotoxins, tobacco) threatened the program, today man-made artificial molecules (endocrine disruptors) can reprogram the visibly stable program, by a single encounter with hormone receptors at the periods of sensitivity (faulty hormonal imprinting) with life-long consequences (altered cell functions, inclination to diseases, manifestation of diseases, etc., provoked by functional teratogens). The deformed program is inherited to the offspring generations, where further program transformations are taking place on the inherited (transformed) program. As the amount and variants of man-made endocrine disruptors are enormously growing in the human environment and its important parts act during the developmentally most sensitive periods, the diseases provoked by them in adults expectedly will be enormously accruing. Orv Hetil. 2020; 161(25): 1028-1034.


Assuntos
Disruptores Endócrinos/efeitos adversos , Epigênese Genética , Impressão Genômica , Hormônios/metabolismo , Anormalidades Congênitas , Feminino , Hormônios/genética , Humanos , Gravidez , Maturidade Sexual
19.
Nat Rev Genet ; 21(9): 555-571, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32514155

RESUMO

Genomic imprinting and X-chromosome inactivation (XCI) are classic epigenetic phenomena that involve transcriptional silencing of one parental allele. Germline-derived differential DNA methylation is the best-studied epigenetic mark that initiates imprinting, but evidence indicates that other mechanisms exist. Recent studies have revealed that maternal trimethylation of H3 on lysine 27 (H3K27me3) mediates autosomal maternal allele-specific gene silencing and has an important role in imprinted XCI through repression of maternal Xist. Furthermore, loss of H3K27me3-mediated imprinting contributes to the developmental defects observed in cloned embryos. This novel maternal H3K27me3-mediated non-canonical imprinting mechanism further emphasizes the important role of parental chromatin in development and could provide the basis for improving the efficiency of embryo cloning.


Assuntos
Cromossomos Humanos X , Metilação de DNA , Impressão Genômica , Histonas/metabolismo , Inativação do Cromossomo X , Animais , Gametogênese/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Lisina/metabolismo
20.
Adv Neurobiol ; 25: 55-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578144

RESUMO

The chromosome 15q11-q13 region of the human genome is regulated by genomic imprinting, an epigenetic phenomenon in which genes are expressed exclusively from one parental allele. Several genes within the 15q11-q13 region are expressed exclusively from the paternally inherited chromosome 15. At least one gene UBE3A, shows exclusive expression of the maternal allele, but this allele-specific expression is restricted to neurons. The appropriate regulation of imprinted gene expression across chromosome 15q11-q13 has important implications for human disease. Three different neurodevelopmental disorders result from aberrant expression of imprinted genes in this region: Prader-Willi syndrome (PWS), Angelman syndrome (AS), and 15q duplication syndrome.


Assuntos
Síndrome de Angelman , Síndrome de Prader-Willi , Síndrome de Angelman/genética , Cromossomos , Impressão Genômica/genética , Humanos , Síndrome de Prader-Willi/genética
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