Epigenetic marks elucidate gene regulatory elements require for human inhibitory interneuron-like progenitors
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ABSTRACT:
PROVIDER: PRJNA904783 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22397700.fastq.gz | Fastqsanger.gz | |||
| SRR22397701.fastq.gz | Fastqsanger.gz | |||
| SRR22397702.fastq.gz | Fastqsanger.gz | |||
| SRR22397703.fastq.gz | Fastqsanger.gz | |||
| SRR22397704.fastq.gz | Fastqsanger.gz |
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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 inhibitory interneuron cell therapy for chronic focal epilepsy
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Project description:Mesial temporal lobe epilepsy (MTLE) is the most common type of focal seizure disorder. In MTLE, seizures typically originate from a sclerotic hippocampus. Approximately one-third of patients do not respond to anti-seizure drugs and have few effective therapeutic options. Surgery to resect or ablate the affected temporal lobe is one such option, but it is not indicated or adequate for all individuals and can have adverse effects. Here, we report the development of an alternative cell therapy strategy for drug-resistant MTLE. The cell therapeutic is derived from a clinical-grade human embryonic stem cell line, and composed of cryopreserved post-mitotic medial ganglionic eminence (MGE)-type GABAergic inhibitory neurons of a predominantly pallial interneuron lineage. Single-dose intrahippocampal delivery of cryopreserved human pallial interneurons in a chronic mouse model of drug-resistant MTLE resulted in consistent and stable suppression of mesiotemporal seizures, with most animals becoming seizure-free. The grafted human interneurons distributed locally, matured, and persisted in the sclerotic hippocampus throughout the 8.5-month study. Pathological hallmarks of MTLE, such as hippocampal granule cell dispersion and sclerosis, were significantly reduced, and epileptic animal survival rates increased, after administration of the human interneurons. Suppression of seizure activity and amelioration of neuropathology were dose-dependent and suggested a broad therapeutic dosing range. No ectopic tissue or teratoma formation was detected after cell transplantation. Furthermore, behavioral abnormalities were not observed at any dose on a battery of assays. These findings support further development of human pallial MGE-type GABAergic interneuron cell therapy for the treatment of drug-resistant focal epilepsies.
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Project description:Studies in chicks and mice have suggested that transcription factors mark functional subtypes of interneurons in the developing spinal cord. We used genetic, morphological, and physiological studies to test this proposed association in zebrafish. We found that Engrailed-1 expression uniquely marks a class of ascending interneurons, called circumferential ascending (CiA) interneurons, with ipsilateral axonal projections in both motor and sensory regions of spinal cord. These cells express the glycine transporter 2 gene and are the only known ipsilateral interneurons positive for this marker of inhibitory transmission. Patch recordings show that the CiA neurons are rhythmically active during swimming. Pairwise recordings from the CiA interneurons and postsynaptic cells reveal that the Engrailed-1 neurons produce monosynaptic, strychnine-sensitive inhibition of dorsal sensory interneurons and also inhibit more ventral neurons, including motoneurons and descending interneurons. We conclude that Engrailed-1 expression marks a class of inhibitory interneuron that seems to provide all of the ipsilateral glycinergic inhibition in the spinal cord of embryonic and larval fish. Individual Engrailed-1-positive cells are multifunctional, playing roles in both sensory gating and motor pattern generation. This primitive cell type may have given rise to several, more specialized glycinergic inhibitory interneurons in birds and mammals. Our data support the view that the subdivision of spinal cord into different regions by transcription factors defines a primitive functional organization of spinal interneurons that formed a developmental and evolutionary foundation on which more complex systems were built.
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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.
2014-10-07 | E-GEOD-56996 | biostudies-arrayexpress
Project description:The mammalian cerebral cortex comprises a complex neuronal network that maintains a delicate balance between excitatory neurons and inhibitory interneurons. Previous studies, including our own research, have shown that specific interneuron subtypes are closely associated with particular pyramidal neuron types, forming stereotyped local inhibitory microcircuits. However, the developmental processes that establish these precise networks are not well understood. Here we show that pyramidal neuron types are instrumental in maintaining the terminal differentiation and survival of specific associated interneuron subtypes. In a wild-type cortex, the relative abundance of different interneuron subtypes aligns precisely with the pyramidal neuron types with which they synaptically target. In Fezf2 mutant cortex, characterized by the absence of layer 5 pyramidal tract neurons and an expansion of layer 6 intratelencephalic neurons, we observed a corresponding decrease in associated layer 5b interneurons and an increase in layer 6 subtypes. Interestingly, these shifts in composition are achieved through mechanisms that are specific to different interneuron types. While SST interneurons adjust their abundance to the change in pyramidal neuron prevalence through the regulation of programmed cell death, parvalbumin cells alter their identity. These findings illustrate two key strategies by which the dynamic interplay between pyramidal neurons and interneurons allows local microcircuits to be sculpted precisely. These insights underscored the precise roles of extrinsic signals from pyramidal cells in the establishment of interneuron diversity and their subsequent integration into local cortical microcircuits.
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Project description:To investigate the novel link between CP-AMPARs and excitability, we assessed global PV interneuron transcriptome changes with FICSR-seq (Fixation-Capture Single Cell RNA Recovery-seq) on forebrain PV interneurons. FACS-assisted PV interneuron bulk RNA-seq of PV-Cre;lsl-eGFP-GluA2 mice and PV-Cre;lsl-eGFP controls showed no expression changes in 278 out of 279 genes comprising the major classes of ion channels and excitatory/inhibitory synapse proteins. This lack of expression changes suggests a post-transcriptional regulation of intrinsic and extrinsic (synaptic) excitability. The exception was GluA2 mRNA, which was expressed ~2 fold compared to control PV interneurons, in agreement with protein measurements. GluA1, although downregulated at protein level, was unchanged at the mRNA level. These transcriptomic results suggest that the substantial changes in PV interneuron excitability after CP-AMPAR removal are not supported by changes in gene expression but likely reflect post-transcriptional regulation.
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