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Comparison of WT and CHD2 haploinsufficent human interneuron progenitor (hMGE) and interneuron (hcIN) models, to define differences in RNA expression, genomic accessibility and histone 3 lysine 27 acetylation

ABSTRACT: Background: Mutations in the chromatin remodeller CHD2 have been strongly associated with multiple neurodevelopmental disorders. However the precise function of CHD2 through neuronal development remains largely uncharacterized. Methods: We have used our protocol for generating cortical interneurons from human embryonic stem cells to study the role of CHD2 in cortical interneuron development, by comparing wild type hMGE and hcINs with a model with CHD2 haploinsufficency Results: This work found that CHD2 controls the expresson of genes with rolls in cell-cell interaction in neuronal precursors and directly influences the exprssion of genes necessary for the production of post-mitotic cortical interneurons Conclusions: As CHD2 plays distinct roles in several aspects of interneuron development, pathogenic CHD2 mutations have high potential to disrupt one or more of these events, contributing to neurodevelopmental disorders

ORGANISM(S): Homo sapiens

PROVIDER: GSE182770 | GEO | 2022/09/21

REPOSITORIES: GEO

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Characterization of CHD2 binding, H3K27ac, H3K27me3 and H3K4me3 in hESC, hMGE and hcIN

Project description:Background: Mutations in the chromatin remodelling protein CHD2 have been strongly associated with multiple neurodevelopmental disorders. However the precise function of CHD2 through neuronal development remains largely uncharacterized. Methods: We have used our protocol for generating cortical interneurons from human embryonic stem cells to study the role of CHD2 in brain development Results: This work found that CHD2 binding is largely associated with open and active chromatin Conclusions: As CHD2 plays distinct roles in several aspects of interneuron development, pathogenic CHD2 mutations have high potential to disrupt one or more of these events, contributing to NDDs.

2022-09-21 | GSE182771 | GEO

Chd2 is necessary for neural circuit development and long-term memory

Project description:Considerable evidence suggests loss of function mutations in the chromatin remodeler, CHD2, contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show Chd2+/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2+/- mice, including alterations in neurogenesis, synaptic transmission and disease-related genes. Deficits in interneuron density and memory caused by Chd2+/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory.

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Cell-intrinsic regulation of interneuron migration controls cortical neurogenesis

Project description:Interneurons navigate along multiple tangential paths to settle into appropriate cortical layer. They undergo saltatory migration, which is paced by intermittent nuclear jumps whose regulation relies on interplay between extracellular cues and genetic-encoded information. However, it remains unclear how cycles of pause and movement are coordinated at the molecular level. Post-translational modification of proteins contributes to cell migration regulation. The present study uncovers that carboxypeptidase 1, which promotes deglutamylation, is a pivotal regulator of pausing of cortical interneurons. Moreover, we show that pausing during migration controls the flow of interneurons invading the cortex by generating heterogeinity in movement at the population level. Interfering with the regulation of pausing not only affects the size of the cortical interneuron cohort but also secondarily impairs the generation of age-matched upper layer projection neurons.

2018-02-14 | PXD006397 | Pride

Comparative analysis of different cortical interneuron groups.

Project description:GABAergic interneuron in the cortex comprise a very heterogenous group. and it is critical to identify discrete interneuron types to understand how their contributions to behavior can be modulated by external and internal cues. However, molecular difinition of these interneuron cell groups has been difficult. Comparative analysis of different interneuron subtypes can provide us new candidate marker genes which could target more specific interneu?on cell group. Here we identify oxytocin responsive novel class of interneuron through our comparative analysis. We employed the bacTRAP strategy, which uses BAC transgenic mice expressing EGFP-tagged ribosomal protein L10a in specific cell populations, to affinity purify polysome-bound mRNAs from Nek7, Dlx1, Cort, Htr3a, Oxtr expressing cortical interneurons. We show that Oxtr expressing cells are a subtype of somatostatin positive interneurons. Three independent TRAP replicates were collected and total RNA from the immunoprecipitates or flow-through (input) whole cortex lysates were amplified and hybridized. Data were normalized with the GCRMA algorithm and replicates were averaged across conditions. We recommend filtering data to remove probe sets with normalized expression values less than 50 in at least one condition. Because the Nek7 BAC labels non-neuronal cells, we recommend to delete astrocytes and oligodendrocytes genes from the list using GSE13379 data.

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Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2

Project description:Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2

| PRJNA757766 | ENA

Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development

Project description:Human embryonic stem cells (hESCs) were specified as ventral telencephalic neuroectoderm (day 4) and then into medial ganglionic emininence (MGE)-like progenitors (day 15) and were subsequently differentiated into cortical interneuron (cIN)-like cells (day 25-35), by modification of previously published protocols. RNA-seq analysis at days 0, 4, 15, 25, and 35 defined transcriptome signatures for MGE and cIN cell identity. Further integration of these gene expression signatures with ChIP-seq for the NKX2-1 transcription factor in MGE-like progenitors defined NKX2-1 putative direct targets, including genes involved in both MGE specification and in several aspects of later cIN differentiation (migration, synaptic function). Among the NKX2-1 direct targets with MGE and cIN enriched expression was CHD2, a chromatin remodeling protein. Since CHD2 haploinsufficiency can cause epilepsy and/or autism, which can involve altered cIN development or function, we evaluated CHD2 requirements in these processes. Transcriptome changes were evaluated in CHD2 knockdown MGE-like progenitors at day 15, revealing diminished expression of genes involved in MGE specification and cIN differentiation including channel and synaptic genes implicated in epilepsy, while later cIN electrophysiological properties were also altered. We defined some shared cis-regulatory elements bound by both NKX2-1 and CHD2 and characterized their ability to cooperatively regulate cIN gene transcription through these elements. We used these data to construct regulatory networks underlying MGE specification and cIN differentiation and to define requirements for CHD2 and its ability to cofunction with NKX2-1 in this process.

2017-11-30 | GSE99937 | GEO

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Project description:We have used our protocol for generating cortical interneurons from human embryonic stem cells (hESCs) to study gene expression changes during this process, to identify regulatory networks critical to cortical interneuron development. Samples were collected at day 0 (hESCs), day 15 (ventral telencephalic patterned medial ganglionic eminence-like progenitors), day 35 (immature interneurons), and day 60 (mature interneurons).

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Epigenetic marks elucidate gene regulatory elements require for human inhibitory interneuron-like progenitors

Project description:Gene regulatory elements such as enhancers dynamically regulate gene expression in a tissue-specific manner. However, the transcriptional regulatory elements during human inhibitory interneuron differentiation and their role in neurodevelopmental disorders are unknown. Here, we generate gene regulatory element maps of human inhibitory-like interneurons derived from embryonic stem cells (H9-ESC), permitting large-scale annotation of previously uncharacterized regulatory elements relevant to inhibitory interneuron differentiation. Our analyses identify neuronal progenitor enhancers that likely regulate the expression of transcription factors that are essential for interneuron differentiation. Focusing on dynamic changes in chromatin organization, FOXG1 and ZEB2, where the chromatin organization is changed in interneuron progenitors compared to different stages during the differentiation. Using 4C-seq and an in vivo enhancer assay, we characterized neuronal enhancers at the FOXG1 locus that interact with the FOXG1 promoter region and showed activity patterns that resemble FOXG1 expression. Using CRISPR/Cas9 genome editing, we deleted FOXG1 enhancer/s that reduced FOXG1 expression in glioblastoma cells and altered cell proliferation. Furthermore, a microdeletion proximal to FOXG1 encompassing these neuronal FOXG1 enhancers was found in a patient with Rett-like syndrome, supporting the role of FOXG1 enhancers in this syndrome. Thus, our study elucidates the gene regulatory networks of human inhibitory interneurons. Furthermore, it provides a framework for understanding the impact of non-coding regulatory elements during inhibitory interneuron differentiation, and highlights novel mechanisms underlying neurodevelopmental disorders.

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Project description:Human embryonic stem cells with a GFP reporter knock-in into the NKX2.1 locus were differentiated and purified by FACS sorting for global gene expression analysis. Directed differentiation from human pluripotent stem cells (hPSCs) has seen significant progress in recent years. Most differentiated populations, however, exhibit immature properties of an early embryonic stage, raising concerns about their ability to model and treat disease. Here, we report the directed differentiation of hPSCs into medial ganglionic eminence (MGE)-like progenitors and their maturation into forebrain type interneurons. We find that early stage progenitors progress via a radial glial-like stem cell enriched in the human fetal brain. Both in vitro and post-transplantation into the rodent cortex, the MGE-like cells develop into GABAergic interneuron subtypes with mature physiological properties along a prolonged intrinsic timeline of up to seven months, mimicking endogenous human neural development. MGE-derived cortical interneuron deficiencies are implicated in a broad range of neurodevelopmental and degenerative disorders, highlighting the importance of these results for modeling human neural development and disease. Human embryonic stem cells with a GFP reporter knock-in into the NKX2.1 locus were differentiated for 20, 35, and 55 days in vitro and GFP+ cells were purified by FACS sorting. Total RNA was prepared from each timepoint and compared to undifferentiated human embryonic stem cells. hESC = one sample and three technical replicates. D20 = three independent samples. D35 = one sample and two technical replicates. D55 = one sample and one technical replicate.

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Comparative analysis of different cortical interneuron groups.

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