Publications by authors named "Dag Yasui"

Article Synopsis
  • Female X-linked diseases are rare due to X chromosome inactivation, but Rett syndrome (RTT) is an exception caused by MECP2 mutations.
  • In a study using mutant mice, researchers found sex differences in gene expression, with mutant females showing significantly more altered genes than males, even before symptoms appeared.
  • The study highlights the importance of both cell type and interactions between different cell types in understanding RTT progression, suggesting potential avenues for treatment.
View Article and Find Full Text PDF

As genome sequencing technologies advance, the accumulation of sequencing data in public databases necessitates more robust and adaptable data analysis workflows. Here, we present Rocketchip, which aims to offer a solution to this problem by allowing researchers to easily compare and swap out different components of ChIP-seq, CUT&RUN, and CUT&Tag data analysis, thereby facilitating the identification of reliable analysis methodologies. Rocketchip enables researchers to efficiently process large datasets while ensuring reproducibility and allowing for the reanalysis of existing data.

View Article and Find Full Text PDF

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that terminates at PWAR1 in non-neurons. qRT-PCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing.

View Article and Find Full Text PDF

Background: Autism spectrum disorder comprises a group of neurodevelopmental conditions currently diagnosed by behavioral assessment in childhood, although neuropathology begins during gestation. A poorly understood male bias for ASD diagnosis is thought to be due to both biological sex differences and cultural biases against female diagnosis of ASD. Identification of molecular biomarkers of ASD likelihood in newborns would provide more objective screening and early intervention.

View Article and Find Full Text PDF
Article Synopsis
  • Dominant X-linked diseases, like Rett syndrome (RTT), are rare because females have X chromosome inactivation, which usually protects against such mutations.
  • RTT is a neurodevelopmental disorder that appears in girls after a period of normal development, leading to a regression of skills that researchers still don't fully understand.
  • A study using single-nucleus RNA sequencing on a mouse model of RTT found significant sex differences in gene expression, revealing that mutant females had more affected genes than males, which could be vital for understanding disease progression and potential treatments.
View Article and Find Full Text PDF

Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing.

View Article and Find Full Text PDF
Article Synopsis
  • - Polychlorinated biphenyls (PCBs) are toxic chemicals linked to developmental neurotoxic effects, particularly related to neurodevelopmental disorders (NDDs).
  • - Research shows that prenatal PCB exposure alters DNA methylation patterns in mouse placentas and fetal brains, revealing thousands of differentially methylated regions (DMRs) that enhance neurodevelopment functions.
  • - Notably, the affected regions in both placenta and brain significantly overlap, linking them to genes involved in important signaling pathways associated with NDDs, and these findings are consistent with similar patterns observed in humans.
View Article and Find Full Text PDF

Background: Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome.

View Article and Find Full Text PDF
Article Synopsis
  • Rett syndrome (RTT) is a disorder primarily affecting girls, leading to various complications, including issues with gut health and metabolism, linked to mutations in the MECP2 gene.
  • Researchers used a mouse model specifically tailored for RTT to compare the development of the disease in both male and female mice, focusing on gut microbiomes and metabolic changes over time.
  • The study found that female mice showed significant early metabolic alterations and gut microbial changes related to RTT, which were not seen in males, highlighting the importance of studying female models to understand RTT better.
View Article and Find Full Text PDF

MeCP2 protein, encoded by the gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with gene mutations.

View Article and Find Full Text PDF

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) of high-risk pregnancies.

View Article and Find Full Text PDF

Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2.

View Article and Find Full Text PDF

Prader-Willi syndrome (PWS), an imprinted neurodevelopmental disorder characterized by metabolic, sleep and neuropsychiatric features, is caused by the loss of paternal SNORD116, containing only non-coding RNAs (ncRNAs). The primary SNORD116 transcript is processed into small nucleolar RNAs (snoRNAs), which localize to nucleoli, and their spliced host gene 116HG, which is retained at its site of transcription. While functional complementation of the SNORD116 ncRNAs is a desirable goal for treating PWS, the mechanistic requirements of SNORD116 RNA processing are poorly understood.

View Article and Find Full Text PDF

Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans.

View Article and Find Full Text PDF

Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. Here, we show a major genetic effect on rhythmic methylation in a mouse Snord116 deletion model of the imprinted disorder Prader-Willi syndrome (PWS).

View Article and Find Full Text PDF

Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood.

View Article and Find Full Text PDF

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams.

View Article and Find Full Text PDF

Rare variants enriched for functions in chromatin regulation and neuronal synapses have been linked to autism. How chromatin and DNA methylation interact with environmental exposures at synaptic genes in autism etiologies is currently unclear. Using whole-genome bisulfite sequencing in brain tissue and a neuronal cell culture model carrying a 15q11.

View Article and Find Full Text PDF

Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a 'prototypical' neurodevelopmental disorder with many clinical features overlapping with other intellectual and developmental disabilities (IDD). Therapeutic interventions for RTT may therefore have broader applications.

View Article and Find Full Text PDF

Methyl-CpG binding protein 2 (MeCP2) is critical for proper brain development and expressed at near-histone levels in neurons, but the mechanism of its genomic localization remains poorly understood. Using high-resolution MeCP2-binding data, we show that DNA sequence features alone can predict binding with 88% accuracy. Integrating MeCP2 binding and DNA methylation in a probabilistic graphical model, we demonstrate that previously reported genome-wide association with methylation is in part due to MeCP2's affinity to GC-rich chromatin, a result replicated using published data.

View Article and Find Full Text PDF

During postnatal development, neuronal activity controls the remodeling of initially imprecise neuronal connections through the regulation of gene expression. MeCP2 binds to methylated DNA and modulates gene expression during neuronal development and MECP2 mutation causes the autistic disorder Rett syndrome. To investigate a role for MeCP2 in neuronal circuit refinement and to identify activity-dependent MeCP2 transcription regulations, we leveraged the precise organization and accessibility of olfactory sensory axons to manipulation of neuronal activity through odorant exposure in vivo.

View Article and Find Full Text PDF

Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression.

View Article and Find Full Text PDF

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT.

View Article and Find Full Text PDF

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted autism-spectrum disorders with known genetic bases, but complex epigenetic mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11-q13 is regulated by an imprinting control region that is maternally methylated and silenced. The PWS imprinting control region is the promoter for a one megabase paternal transcript encoding the ubiquitous protein-coding Snrpn gene and multiple neuron-specific noncoding RNAs, including the PWS-related Snord116 repetitive locus of small nucleolar RNAs and host genes, and the antisense transcript to AS-causing ubiquitin ligase encoding Ube3a (Ube3a-ATS).

View Article and Find Full Text PDF