scholarly journals The Autism Risk Factor CHD8 Is a Chromatin Activator in Human Neurons and Functionally Dependent on the ERK-MAPK Pathway Effector ELK1

2021 ◽  
Author(s):  
Bahareh Haddad Derafshi ◽  
Tamas Danko ◽  
Soham Chanda ◽  
Pedro Batista ◽  
Ulrike Litzenburger ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
De Novo ◽  
Mapk Pathway ◽  
Transcriptional Profiling ◽  
Distinct Group ◽  
Chromatin Accessibility ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Human Neurons

Abstract The chromodomain helicase DNA-binding protein CHD8 is among the most frequently found de-novo mutations in autism spectrum disorder (ASD)1-4. Despite its prominent disease involvement, little is known about its molecular function in the human brain. CHD8 is believed to be a chromatin regulator, but mechanisms for its genomic targeting is also unclear. To elucidate the role of CHD8 in human neurons, we generated conditional loss-of-function alleles in pluripotent stem cells. Chromatin accessibility and transcriptional profiling showed that CHD8 is a potent chromatin opener and transcriptional activator of its direct neuronal targets, including a distinct group of ASD genes. We found the chromatin targeting of CHD8 to be highly context dependent. In human neurons, CHD8 was preferentially bound at promoter sequences which were significantly enriched in ETS motifs. Indeed, the chromatin state of ETS motif-containing promoters was preferentially affected upon loss of CHD8. Among the many ETS transcription factors, we found ELK1 to be the best correlated with CHD8 expression in primary human fetal and adult cortical neurons and most highly expressed in our ES cell-derived neurons. Remarkably, ELK1 was necessary to recruit CHD8 specifically to ETS motif-containing sites. These findings imply the functional cooperativity between ELK1, a key downstream factor of the MAPK/ERK pathway, and CHD8 on chromatin involvement in human neurons. THEREFORE, the MAPK/ERK/ELK1 axis may also play a role in the pathogenesis caused by CHD8 mutations5 .

scholarly journals The Autism Risk Factor CHD8 Is a Chromatin Activator and Functionally Dependent on the ERK-MAPK Pathway Effector ELK1

2020 ◽  
Author(s):  
Bahareh Haddad Derafshi ◽  
Tamas Danko ◽  
Soham Chanda ◽  
Pedro Batista ◽  
Ulrike Litzenburger ◽  
...  
Keyword(s):  
Binding Sites ◽  
De Novo ◽  
Cell Model ◽  
Mapk Pathway ◽  
Es Cells ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Cooperative Interaction ◽  
Dependent Manner ◽  
Human Neurons

AbstractThe chromodomain helicase DNA-binding protein CHD8 is among the most frequently found de-novo mutations in autism (1–3). Unlike most other autism-risk genes, CHD8 mutations appear to be fully penetrant (4). Despite its prominent disease involvement, little known about its molecular function. Based on sequence homology, CHD8 is believed to be a chromatin regulator, but mechanisms for its genomic targeting and its role on chromatin are unclear. Here, we developed a human cell model carrying conditional CHD8 loss-of-function alleles. Full knockout CHD8 was required for the viability of undifferentiated human embryonic stem (ES) cells, whereas postmitotic neurons survived following CHD8 depletion. However, chromatin accessibility maps and transcriptional profiling revealed that CHD8 is a potent general chromatin activator, enhancing transcription of its direct target genes, including a large group of autism genes. CHD8’s genomic binding sites in human neurons were significantly enriched for ELK1 (ETS) motifs. Moreover, positive CHD8-dependent chromatin remodeling was enhanced at ELK1 motif-containing CHD8 binding sites. ELK1 was the most prominent ETS factor expressed in human neurons and was necessary for CHD8 to target the sites that contained the ELK1 motif, demonstrating a cooperative interaction between ELK1 and CHD8 on chromatin. We also observed potential role of CHD8 in ELK1 localization on nuclear compartments in a transcription-stage-dependent manner. Finally, inhibition of ELK1 activity or ELK1 knockdown that enhances the neurogenesis from embryonic stem cells (ES) was dependent on the presence of CHD8. In summary, our results establish that CHD8 is a strong activator of chromatin accessibility and transcription in neurons and reveals a role in regulating many high-risk autism genes. Additionally, we show there is molecular and functional interdependence of CHD8 and ELK1 in chromatin binding of CHD8, nuclear interaction of ELK1, and neurogenesis enhancement. These data imply the involvement of the MAPK/ERK pathway effector ELK1 in pathogenesis of autism caused by CHD8 mutations (5).

scholarly journals P.135 Autism-associated mutations in SHANK2 increase synaptic connectivity and dendrite complexity in human neurons

2018 ◽  
Vol 45 (s2) ◽  
pp. S52-S52
Author(s):  
K Zaslavsky ◽  
W Zhang ◽  
E Deneault ◽  
M Zhao ◽  
DC Rodrigues ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Autism Spectrum ◽  
Dermal Fibroblasts ◽  
Neuronal Morphology ◽  
Synaptic Connectivity ◽  
Loss Of Function ◽  
Knock Out ◽  
Electrophysiological Properties ◽  
Dendrite Length ◽  
Human Neurons

Background: Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). However, their impact on the function of human neurons is unknown. Derivation of induced pluripotent stem cells (iPSC) from affected individuals permits generation of live neurons to answer this question. Methods: We generated iPSCs by reprogramming dermal fibroblasts of neurotypic and ASD-affected donors. To isolate the effect of SHANK2, we used CRISPR/Cas9 to knock out SHANK2 in control iPSCs and correct a heterozygous nonsense mutation in ASD-affected donor iPSCs. We then derived cortical neurons from SOX1+ neural precursor cells differentiated from these iPSCs. Using a novel assay that overcomes line-to-line variability, we compared neuronal morphology, total synapse number, and electrophysiological properties between SHANK2 mutants and controls. Results: Relative to controls, SHANK2 mutant neurons have increased dendrite complexity, dendrite length, total synapse number (1.5-2-fold), and spontaneous excitatory postsynaptic current (sEPSC) frequency (3-7.6-fold). Conclusions: ASD-associated heterozygous loss-of-function mutations in SHANK2 increase synaptic connectivity among human neurons by increasing synapse number and sEPSC frequency. This is partially supported by increased dendrite length and complexity, providing evidence that SHANK2 functions as a suppressor of dendrite branching during neurodevelopment.

scholarly journals Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

2021 ◽  
Author(s):  
Eirene Markenscoff ◽  
Fadya Binyameen ◽  
Sean Whalen ◽  
James Price ◽  
Kenneth Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Cortical Function ◽  
Risk Gene ◽  
Chromatin Regulator

De novo mutations in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Here we find that in the developing mouse and human brain POGZ binds predominantly euchromatic loci and these are enriched for human neurodevelopmental disorder genes and transposable elements. We profile chromatin accessibility and gene expression in Pogz-/- mice and find that POGZ promotes chromatin accessibility of candidate regulatory elements (REs) and the expression of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with HP1gamma and ADNP, another high-confidence ASD risk gene. In Pogz+/- mice, Adnp expression is reduced. We postulate that reduced POGZ dosage disrupts cortical function through alterations in the POGZ-ADNP balance which modifies neuronal gene expression.

scholarly journals A Bibliometric Insight of Genetic Factors in ASD: Emerging Trends and New Developments

2020 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Kang Wang ◽  
Weicheng Duan ◽  
Yijie Duan ◽  
Yuxin Yu ◽  
Xiuyi Chen ◽  
...  
Keyword(s):  
Genetic Factors ◽  
De Novo ◽  
Rapid Development ◽  
The United States ◽  
Research Area ◽  
Scientific Output ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Emerging Trends ◽  
Genetic Abnormalities

Autism spectrum disorder (ASD) cases have increased rapidly in recent decades, which is associated with various genetic abnormalities. To provide a better understanding of the genetic factors in ASD, we assessed the global scientific output of the related studies. A total of 2944 studies published between 1997 and 2018 were included by systematic retrieval from the Web of Science (WoS) database, whose scientific landscapes were drawn and the tendencies and research frontiers were explored through bibliometric methods. The United States has been acting as a leading explorer of the field worldwide in recent years. The rapid development of high-throughput technologies and bioinformatics transferred the research method from the traditional classic method to a big data-based pipeline. As a consequence, the focused research area and tendency were also changed, as the contribution of de novo mutations in ASD has been a research hotspot in the past several years and probably will remain one into the near future, which is consistent with the current opinions of the major etiology of ASD. Therefore, more attention and financial support should be paid to the deciphering of the de novo mutations in ASD. Meanwhile, the effective cooperation of multi-research centers and scientists in different fields should be advocated in the next step of scientific research undertaken.

Review of treatment and therapeutic targets in brain arteriovenous malformation

2021 ◽  
pp. 0271678X2110267
Author(s):  
Peipei Pan ◽  
Shantel Weinsheimer ◽  
Daniel Cooke ◽  
Ethan Winkler ◽  
Adib Abla ◽  
...  
Keyword(s):  
Animal Models ◽  
De Novo ◽  
Mapk Pathway ◽  
Treatment Options ◽  
Therapeutic Targets ◽  
Current Treatment ◽  
Mitogen Activated Protein Kinase ◽  
De Novo Mutations ◽  
Genetic Syndromes ◽  
Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

scholarly journals De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

2017 ◽  
Vol 114 (35) ◽  
pp. E7341-E7347 ◽  
Author(s):  
Andrew T. Timberlake ◽  
Charuta G. Furey ◽  
Jungmin Choi ◽  
Carol Nelson-Williams ◽  
Erin Loring ◽  
...  
Keyword(s):  
De Novo ◽  
Erk Signaling ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Neurodevelopmental Outcomes ◽  
Locus Heterogeneity ◽  
Syndromic Craniosynostosis ◽  
New Genes ◽  
Morphogenetic Protein ◽  
Nuclear Targets

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10−11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

scholarly journals CACNA1D De Novo Mutations in Autism Spectrum Disorders Activate Cav1.3 L-Type Calcium Channels

2015 ◽  
Vol 77 (9) ◽  
pp. 816-822 ◽  
Author(s):  
Alexandra Pinggera ◽  
Andreas Lieb ◽  
Bruno Benedetti ◽  
Michaela Lampert ◽  
Stefania Monteleone ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Calcium Channels ◽  
De Novo ◽  
Autism Spectrum ◽  
De Novo Mutations ◽  
Spectrum Disorders

scholarly journals Integrating de novo and inherited variants in over 42,607 autism cases identifies mutations in new moderate risk genes

2021 ◽  
Author(s):  
Xueya Zhou ◽  
Pamela Feliciano ◽  
Tianyun Wang ◽  
Irina Astrovskaya ◽  
Chang Shu ◽  
...  
Keyword(s):  
Genetic Risk ◽  
De Novo ◽  
Meta Analysis ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
Moderate Risk ◽  
Full Spectrum ◽  
Risk Genes ◽  
Biological Parents

AbstractDespite the known heritable nature of autism spectrum disorder (ASD), studies have primarily identified risk genes with de novo variants (DNVs). To capture the full spectrum of ASD genetic risk, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases recruited online by SPARK. In the first stage, we analyzed 19,843 cases with one or both biological parents and found that known ASD or neurodevelopmental disorder (NDD) risk genes explain nearly 70% of the genetic burden conferred by DNVs. In contrast, less than 20% of genetic risk conferred by rare inherited loss-of-function (LoF) variants are explained by known ASD/NDD genes. We selected 404 genes based on the first stage of analysis and performed a meta-analysis with an additional 22,764 cases and 236,000 population controls. We identified 60 genes with exome-wide significance (p < 2.5e-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1, and HNRNPUL2). The association of NAV3 with ASD risk is entirely driven by rare inherited LoFs variants, with an average relative risk of 4, consistent with moderate effect. ASD individuals with LoF variants in the four moderate risk genes (NAV3, ITSN1, SCAF1, and HNRNPUL2, n = 95) have less cognitive impairment compared to 129 ASD individuals with LoF variants in well-established, highly penetrant ASD risk genes (CHD8, SCN2A, ADNP, FOXP1, SHANK3) (59% vs. 88%, p= 1.9e-06). These findings will guide future gene discovery efforts and suggest that much larger numbers of ASD cases and controls are needed to identify additional genes that confer moderate risk of ASD through rare, inherited variants.

scholarly journals Identification of a β-Arrestin 2 Mutation Related to Autism by Whole-Exome Sequencing

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yunfei Tang ◽  
Yamei Liu ◽  
Lei Tong ◽  
Shini Feng ◽  
Dongshu Du ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Developmental Stages ◽  
De Novo ◽  
Repetitive Behavior ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Potential Contribution ◽  
De Novo Mutations ◽  
Whole Exome

Autism spectrum disorder (ASD) is a complex neurological disease characterized by impaired social communication and interaction skills, rigid behavior, decreased interest, and repetitive activities. The disease has a high degree of genetic heterogeneity, and the genetic cause of ASD in many autistic individuals is currently unclear. In this study, we report a patient with ASD whose clinical features included social interaction disorder, communication disorder, and repetitive behavior. We examined the patient’s genetic variation using whole-exome sequencing technology and found new de novo mutations. After analysis and evaluation, ARRB2 was identified as a candidate gene. To study the potential contribution of the ARRB2 gene to the human brain development and function, we first evaluated the expression profile of this gene in different brain regions and developmental stages. Then, we used weighted gene coexpression network analysis to analyze the associations between ARRB2 and ASD risk genes. Additionally, the spatial conformation and stability of the ARRB2 wild type and mutant proteins were examined by simulations. Then, we further established a mouse model of ASD. The results showed abnormal ARRB2 expression in the mouse ASD model. Our study showed that ARRB2 may be a risk gene for ASD, but the contribution of de novo ARRB2 mutations to ASD is unclear. This information will provide references for the etiology of ASD and aid in the mechanism-based drug development and treatment.

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