scholarly journals Placental DNA methylation changes and the early prediction of autism in full-term newborns

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253340
Author(s):  
Ray O. Bahado-Singh ◽  
Sangeetha Vishweswaraiah ◽  
Buket Aydas ◽  
Uppala Radhakrishna
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Predictive Accuracy ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Full Term ◽  
Functional Enrichment ◽  
P Value ◽  
Fetal Life ◽  
450K Array

Autism spectrum disorder (ASD) is associated with abnormal brain development during fetal life. Overall, increasing evidence indicates an important role of epigenetic dysfunction in ASD. The placenta is critical to and produces neurotransmitters that regulate fetal brain development. We hypothesized that placental DNA methylation changes are a feature of the fetal development of the autistic brain and importantly could help to elucidate the early pathogenesis and prediction of these disorders. Genome-wide methylation using placental tissue from the full-term autistic disorder subtype was performed using the Illumina 450K array. The study consisted of 14 cases and 10 control subjects. Significantly epigenetically altered CpG loci (FDR p-value <0.05) in autism were identified. Ingenuity Pathway Analysis (IPA) was further used to identify molecular pathways that were over-represented (epigenetically dysregulated) in autism. Six Artificial Intelligence (AI) algorithms including Deep Learning (DL) to determine the predictive accuracy of CpG markers for autism detection. We identified 9655 CpGs differentially methylated in autism. Among them, 2802 CpGs were inter- or non-genic and 6853 intragenic. The latter involved 4129 genes. AI analysis of differentially methylated loci appeared highly accurate for autism detection. DL yielded an AUC (95% CI) of 1.00 (1.00–1.00) for autism detection using intra- or intergenic markers by themselves or combined. The biological functional enrichment showed, four significant functions that were affected in autism: quantity of synapse, microtubule dynamics, neuritogenesis, and abnormal morphology of neurons. In this preliminary study, significant placental DNA methylation changes. AI had high accuracy for the prediction of subsequent autism development in newborns. Finally, biologically functional relevant gene pathways were identified that may play a significant role in early fetal neurodevelopmental influences on later cognition and social behavior.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

scholarly journals A perturbed gene network containing PI3K/AKT, RAS/ERK, WNT/β-catenin pathways in leukocytes is linked to ASD genetics and symptom severity

2018 ◽  
Author(s):  
Vahid H. Gazestani ◽  
Tiziano Pramparo ◽  
Srinivasa Nalabolu ◽  
Benjamin P. Kellman ◽  
Sarah Murray ◽  
...  
Keyword(s):  
Brain Development ◽  
Gene Network ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Typical Development ◽  
Core Network ◽  
Neuron Models ◽  
Risk Genes ◽  
Fetal Brain Development ◽  
Upstream Regulators

ABSTRACTHundreds of genes are implicated in autism spectrum disorder (ASD) but the mechanisms through which they contribute to ASD pathophysiology remain elusive. Here, we analyzed leukocyte transcriptomics from 1-4 year-old male toddlers with ASD or typical development from the general population. We discovered a perturbed gene network that includes genes that are highly expressed during fetal brain development and which is dysregulated in hiPSC-derived neuron models of ASD. High-confidence ASD risk genes emerge as upstream regulators of the network, and many risk genes may impact the network by modulating RAS/ERK, PI3K/AKT, and WNT/β-catenin signaling pathways. We found that the degree of dysregulation in this network correlated with the severity of ASD symptoms in the toddlers. These results demonstrate how the heterogeneous genetics of ASD may dysregulate a core network to influence brain development at prenatal and very early postnatal ages and, thereby, the severity of later ASD symptoms.

scholarly journals Novel Epigenetic Clock for Fetal Brain Development Predicts Fetal Epigenetic Age for iPSCs and iPSC-Derived Neurons.

2020 ◽  
Author(s):  
Leonard C Steg ◽  
Gemma L Shireby ◽  
Jennifer Imm ◽  
Jonathan P Davies ◽  
Robert Flynn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Fetal Brain ◽  
Cell Types ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Age Related ◽  
Epigenetic Age

Abstract Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

scholarly journals Novel epigenetic clock for fetal brain development predicts fetal epigenetic age for iPSCs and iPSC-derived neurons

2020 ◽  
Author(s):  
Leonard C. Steg ◽  
Gemma L. Shireby ◽  
Jennifer Imm ◽  
Jonathan P. Davies ◽  
Robert Flynn ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Fetal Brain ◽  
Cell Types ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Age Related ◽  
Epigenetic Age

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the early stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age, and is has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons, here, we establish the fetal brain clock (FBC), a bespoke epigenetic clock trained in prenatal neurodevelopmental samples. Our data show that the FBC outperforms other established epigenetic clocks in predicting the age of fetal brain samples. We then applied the FBC to DNA methylation data of cellular datasets that have profiled iPSCs and iPSC-derived neuronal precursor cells and neurons and find that these cell types are characterized by a fetal epigenetic age. Furthermore, while differentiation from iPSCs to neurons significantly increases the epigenetic age, iPSC-neurons are still predicted as having fetal epigenetic age. Together our findings reiterate the need for better understanding of the limitations of existing epigenetic clocks for answering biological research questions and highlight a potential limitation of iPSC-neurons as a cellular model for the research of age-related diseases as they might not fully recapitulate an aged phenotype.

ISDN2014_0171: Dynamic and sex‐specific changes in DNA methylation during human fetal brain development

2015 ◽  
Vol 47 (Part_A) ◽  
pp. 50-51
Author(s):  
H. Spiers ◽  
N.J. Bray ◽  
E. Hannon ◽  
L.C. Schalkwyk ◽  
C.C. Wong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Fetal Brain ◽  
Human Fetal Brain ◽  
Fetal Brain Development

scholarly journals Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Leonard C. Steg ◽  
Gemma L. Shireby ◽  
Jennifer Imm ◽  
Jonathan P. Davies ◽  
Alice Franklin ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Brain Development ◽  
Embryonic Stem ◽  
Fetal Brain ◽  
Biological Research ◽  
Epigenetic Clock ◽  
Cellular Model ◽  
Neuronal Precursor Cells ◽  
Epigenetic Age

AbstractInduced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases.

scholarly journals Molecular regulation of fetal brain development in pigs

2021 ◽  
Author(s):  
◽  
Monica P. Strawn
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factor ◽  
Brain Development ◽  
Early Development ◽  
Expression Patterns ◽  
Fetal Brain ◽  
Molecular Regulation ◽  
Fetal Brain Development ◽  
The Brain

Two experiments were conducted to investigate molecular regulation that impacts fetal brain development in pigs. In the first experiment (Chapter 2), gene expression was profiled by RNA sequencing (RNA-seq) to examine the whole transcriptome of the male (M) and female (F) fetal brain at gestation day (d) 45, 60 and 90. The analysis showed fewer differentially expressed genes (DEGs) in the brain of male and female fetuses in earlier gestation (d45-d60) when compared to late gestation (d60-d90). The homeobox (HOX) A5 gene that regulates pattern formation in early development was in the top upregulated DEGs between d45 to d60 in fetuses of both sexes. This study also found HOX B5 and D3 genes were in the top upregulated genes between d45 and d60 of the fetal brain of females, but not males. The second experiment (Chapter 3) investigated DNA methylation in pigs. DNA methylation in the fetal brain of both sexes at the same three gestation days was performed by enzymatic methyl sequencing (EM-seq). Hotspots of methylation in specific chromosomal regions were observed in the analysis. The analysis identified 1,475 sites in the pig genome that were methylated in the fetal brain, irrespective of sex, during development. The same sites were methylated in a canonically correlated manner in the blood of the adult stage, both in sows and boars. This is consistent with the Dilman theory of developmental aging (DevAge), which suggests that aging and early development of the brain are regulated by common molecular processes. A comparative analysis (Chapter 4) compared the gene expression patterns in the fetal brain and placenta between pigs and mice. The analysis identified 112 genes that were expressed (mean FPKM > 10) in the fetal brain of both species but not expressed (mean FPKM < 1) in the placenta of either species, and 10 genes that were expressed in the placenta of both species but not expressed in the fetal brain. In-silico analysis of the transcription factor binding sites in the 500 bp of the upstream DNA of these common genes revealed that they were commonly regulated by the RE1 silencing transcription factor (REST), which is a multifaceted transcription factor that acts as a master regulator of neurogenesis as well as controls neural excitation and the aging processes.

scholarly journals Gestational Factors throughout Fetal Neurodevelopment: The Serotonin Link

2020 ◽  
Vol 21 (16) ◽  
pp. 5850 ◽  
Author(s):  
Sabrina I. Hanswijk ◽  
Marcia Spoelder ◽  
Ling Shan ◽  
Michel M. M. Verheij ◽  
Otto G. Muilwijk ◽  
...  
Keyword(s):  
Brain Development ◽  
Animal Studies ◽  
Fetal Brain ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
Hyperactivity Disorder ◽  
Maternal Genotype ◽  
Brain Structure And Function ◽  
And Function ◽  
And Behavior

Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.

scholarly journals Umbilical cord blood-derived microglia-like cells to model COVID-19 exposure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Steven D. Sheridan ◽  
Jessica M. Thanos ◽  
Rose M. De Guzman ◽  
Liam T. McCrea ◽  
Joy E. Horng ◽  
...  
Keyword(s):  
Brain Development ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Mononuclear Cells ◽  
Fetal Brain ◽  
Fetal Life ◽  
Cell Models ◽  
Blood Mononuclear Cells ◽  
Cord Blood Mononuclear Cells

AbstractMicroglia, the resident brain immune cells, play a critical role in normal brain development, and are impacted by the intrauterine environment, including maternal immune activation and inflammatory exposures. The COVID-19 pandemic presents a potential developmental immune challenge to the fetal brain, in the setting of maternal SARS-CoV-2 infection with its attendant potential for cytokine production and, in severe cases, cytokine storming. There is currently no biomarker or model for in utero microglial priming and function that might aid in identifying the neonates and children most vulnerable to neurodevelopmental morbidity, as microglia remain inaccessible in fetal life and after birth. This study aimed to generate patient-derived microglial-like cell models unique to each neonate from reprogrammed umbilical cord blood mononuclear cells, adapting and extending a novel methodology previously validated for adult peripheral blood mononuclear cells. We demonstrate that umbilical cord blood mononuclear cells can be used to create microglial-like cell models morphologically and functionally similar to microglia observed in vivo. We illustrate the application of this approach by generating microglia from cells exposed and unexposed to maternal SARS-CoV-2 infection. Our ability to create personalized neonatal models of fetal brain immune programming enables non-invasive insights into fetal brain development and potential childhood neurodevelopmental vulnerabilities for a range of maternal exposures, including COVID-19.

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