Single-cell epigenomics reveals mechanisms of human cortical development

Nature, Год журнала: 2021, Номер 598(7879), С. 205 - 213

Опубликована: Окт. 6, 2021

Abstract During mammalian development, differences in chromatin state coincide with cellular differentiation and reflect changes the gene regulatory landscape 1 . In developing brain, cell fate specification topographic identity are important for defining 2 confer selective vulnerabilities to neurodevelopmental disorders 3 Here, identify cell-type-specific accessibility patterns human we used a single-cell assay transposase by sequencing (scATAC-seq) primary tissue samples from forebrain. We applied unbiased analyses genomic loci that undergo extensive cell-type- brain-region-specific during neurogenesis, an integrative analysis predict candidate elements. found cerebral organoids recapitulate most putative enhancer but lack many open regions vivo. Systematic comparison of across brain revealed unexpected diversity among neural progenitor cells cortex implicated retinoic acid signalling neuronal lineage prefrontal cortex. Together, our results reveal contribution emerging type provide blueprint evaluating fidelity robustness as model cortical development.

Язык: Английский

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Co-translational, Post-translational, and Non-catalytic Roles of N-Terminal Acetyltransferases

Molecular Cell, Год журнала: 2019, Номер 73(6), С. 1097 - 1114

Опубликована: Март 1, 2019

Язык: Английский

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Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes

npj Genomic Medicine, Год журнала: 2019, Номер 4(1)

Опубликована: Авг. 23, 2019

Abstract Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by combination of rare de novo and inherited variants as well common in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set genetic risk factors. We conducted pilot study for SPARK (SPARKForAutism.org) 457 families with ASD, all consented online. Whole exome sequencing (WES) genotyping data were generated each family using DNA from saliva. identified genes loci that clinically recognized causes or significant contributors ASD 10.4% without previous findings. In addition, we possibly associated an additional 3.4% families. A meta-analysis TADA framework false discovery rate (FDR) 0.1 provides statistical support 26 While most these already known genes, BRSK2 has strongest reaches genome-wide significance gene ( p -value = 2.3e−06). Future studies leveraging thousands individuals who have enrolled likely further clarify factors allow accelerate research incorporates etiology.

Язык: Английский

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Translation deregulation in human disease

Nature Reviews Molecular Cell Biology, Год журнала: 2018, Номер 19(12), С. 791 - 807

Опубликована: Июль 23, 2018

Язык: Английский

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Alcohol metabolism contributes to brain histone acetylation

Nature, Год журнала: 2019, Номер 574(7780), С. 717 - 721

Опубликована: Окт. 23, 2019

Язык: Английский

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Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism

Molecular Psychiatry, Год журнала: 2018, Номер 24(7), С. 1053 - 1064

Опубликована: Фев. 26, 2018

Differences in cortical morphology—in particular, volume, thickness and surface area—have been reported individuals with autism. However, it is unclear what aspects of genetic transcriptomic variation are associated these differences. Here we investigate the correlates global differences (ΔCT) children We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 (166 autism, 295 neurotypical 87 ADHD) gene expression Allen Institute for Brain Science to identify ΔCT that genes enriched synaptic transmission pathways explain significant ΔCT. These also significantly dysregulated autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected 10−14), driven entirely by downregulated (OR 1.87, 10−15). validated enrichment two independent sets: Validation 1 1.44, 0.004) 2 1.30; 0.001). conclude transcriptionally implicated robustly changes variability

Язык: Английский

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Dendritic Spine Plasticity: Function and Mechanisms

Frontiers in Synaptic Neuroscience, Год журнала: 2020, Номер 12

Опубликована: Авг. 28, 2020

Dendritic spines are small protrusions studding neuronal dendrites, first described in 1888 by Ramón y Cajal using his famous Golgi stainings. Around fifty years later the advance of electron microscopy confirmed Cajal's intuition that constitute postsynaptic site most excitatory synapses mammalian brain. The finding spine density decreases between young and adult ages fixed tissues suggested dynamic. It is only a decade ago two-photon has unambiguously proven dynamic nature spines, through repeated imaging single live animals. Spine dynamics comprise formation, disappearance stabilization modulated activity developmental age. Here we review several emerging concepts field start to answer following key questions: What external signals triggering molecular mechanisms involved? is, return, role circuit rewiring, learning neuropsychiatric disorders?

Язык: Английский

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Candidate biomarkers in psychiatric disorders: state of the field

World Psychiatry, Год журнала: 2023, Номер 22(2), С. 236 - 262

Опубликована: Май 9, 2023

The field of psychiatry is hampered by a lack robust, reliable and valid biomarkers that can aid in objectively diagnosing patients providing individualized treatment recommendations. Here we review critically evaluate the evidence for most promising psychiatric neuroscience literature autism spectrum disorder, schizophrenia, anxiety disorders post‐traumatic stress major depression bipolar substance use disorders. Candidate reviewed include various neuroimaging, genetic, molecular peripheral assays, purposes determining susceptibility or presence illness, predicting response safety. This highlights critical gap biomarker validation process. An enormous societal investment over past 50 years has identified numerous candidate biomarkers. However, to date, overwhelming majority these measures have not been proven sufficiently reliable, useful be adopted clinically. It time consider whether strategic investments might break this impasse, focusing on limited number candidates advance through process definitive testing specific indication. Some N170 signal, an event‐related brain potential measured using electroencephalography, subgroup identification within disorder; striatal resting‐state functional magnetic resonance imaging (fMRI) measures, such as connectivity index (SCI) abnormalities (FSA) index, prediction schizophrenia; error‐related negativity (ERN), electrophysiological first onset generalized structural connectomic social disorder. Alternate forms classification may conceptualizing Collaborative efforts allowing inclusion biosystems beyond genetics neuroimaging are needed, online remote acquisition selected naturalistic setting mobile health tools significantly field. Setting benchmarks well‐defined target application, along with development appropriate funding partnership mechanisms, would also crucial. Finally, it should never forgotten that, actionable, will need clinically predictive at individual level viable clinical settings.

Язык: Английский

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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Nature Communications, Год журнала: 2020, Номер 11(1)

Опубликована: Окт. 1, 2020

Most genes associated with neurodevelopmental disorders (NDDs) were identified an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 16,294 NDD cases and additional 62 6,211 cases. By combining these published data, assess a total 125 over 16,000 compare to nonpsychiatric controls from ExAC. We identify 48 (25 newly reported) showing significant ultra-rare (MAF < 0.01%) gene-disruptive (FDR 5%), six which reach family-wise error rate (FWER) (p 1.25E-06). Among targeted genes, also reevaluate DNM 17,426 trios 6,499 new autism trios. 90 enriched for DNMs 5%; e.g., GABRG2 UIMC1); which, 61 FWER 3.64E-07; CASZ1). In addition doubling number patients many risk present phenotype-genotype correlations seven (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, LEO1) based on this large-scale sequencing effort.

Язык: Английский

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Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder

Cell Reports, Год журнала: 2018, Номер 22(3), С. 734 - 747

Опубликована: Янв. 1, 2018

Highlights•Exome sequencing of Japanese ASD trios supports "de novo paradigm"•Integrative analyses were conducted by combining with published DNM data•Integrative confirm and extend ASD-related molecular brain networks•Integrative identify 61 significant genes as well drug candidatesSummaryRecent studies have established important roles de mutations (DNMs) in autism spectrum disorders (ASDs). Here, we analyze DNMs 262 probands origin the paradigm" ASDs across ethnicities. Based on this consistency, combine lists damaging our cohorts (total number trios, 4,244) perform integrative bioinformatics analyses. Besides replicating findings previous studies, highlight ATP-binding fetal cerebellar/striatal circuits. Analysis individual identified enriched for DNMs, including ten which dataset now contributes to statistical significance. Screening compounds altering expression hit reveals a global downregulating effect valproic acid, known risk factor ASDs, whereas cardiac glycosides upregulate these genes. Collectively, approach provides deeper biological potential medical insights into ASDs.Graphical abstract

Язык: Английский

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