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Modeling endogenous HTT/mHTT pathogenesis in fibroblasts and striatal GABAergic neurons from a Mongolian family with Huntington’s disease

ABSTRACT: Modeling endogenous HTT/mHTT pathogenesis in fibroblasts and striatal GABAergic neurons from a Mongolian family with Huntington’s disease

PROVIDER: PRJNA763815 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15913250_1.fastq.gz	Fastqsanger.gz
	SRR15913250_2.fastq.gz	Fastqsanger.gz
	SRR15913251_1.fastq.gz	Fastqsanger.gz
	SRR15913251_2.fastq.gz	Fastqsanger.gz
	SRR15913252_1.fastq.gz	Fastqsanger.gz

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Impaired inhibitory GABAergic synaptic transmission and transcription studied in single neurons by Patch-seq in Huntington’s disease

Project description:Transcriptional dysregulation in Huntington’s disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-seq in an in vitro HD model to investigate the effects of mutant huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes, whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at single-cell level and to provide a platform for screening for therapeutics for the disease.

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ChIP-seq of HTT protein in mouse cortex following HTT knockdown

Project description:Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of the HD mutation (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3), a marker of poised and active promoters, and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD.

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Transcriptional profiling of mouse embryonic stem cells without Huntingtin (Htt)

Project description:Mutation in the huntingtin (HTT) gene causes Huntington’s disease. Wild type Htt is essential for development as Htt knockout mice die at day E7.5. Increasing evidence suggests mutant Htt may alter neurogenesis and development of striatal neurons resulting in neuronal loss. Using mouse embryonic stem cells (mESCs), we examined the role of Htt in neural differentiation. We found Htt-null (HN) mESCs inefficient in generating neural stem cells. In contrast differentiation into progenitors of mesoderm and endoderm lineages was not affected. To investigate the basis for the lack of neural differentiation, we carried out gene expression profiling by RNA-seq to examine if genes involved in neural differentiation were dysregulated in HN mESCs.

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Modeling endogenous HTT/mHTT pathogenesis in fibroblasts and striatal GABAergic neurons from a Mongolian family with Huntington’s disease

Project description:Single cell RNA-seq and bulk RNA-seq characterization of human induced pluripotent stem cell (hiPSCs) derived Huntington's disease organoids resembling the human striatum

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Mono and biallelic inactivation of Huntingtin gene in patient-specific iPS cells reveal HTT roles in striatal development and in neuronal functions impaired in Huntington’s disease

Project description:Mutations in the Huntingtin (HTT) gene cause Huntington disease (HD), a neurodegenerative disorder. While HTT is known to be involved, as a scaffold protein, in several cellular functions, its normal and pathogenic functions during the development of the human forebrain remain poorly understood. To investigate the roles of wild-type and mutant HTT alleles during human neural and striatal development we inactivated HTT alleles in a series of isogenic clones of a human induced pluripotent stem cell (iPSC) line derived from a patient with HD. We show that the loss of wild-type, mutant, or both HTT isoforms did not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss caused division impairments in forebrain neuro-epithelial cells. Moreover, HTT-/- derivatives displayed impaired maturation of medium spiny neurons (MSNs) particularly in the acquisition of DARPP32 expression, a key functional marker of MSNs. Finally, we discovered that MSNs and cortical neurons derived from HTT-/- clones exhibited higher levels of baseline DNA damage and lower BDNF axonal transport, two cellular dysfunctions previously described in HD neurons.

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Analysis of striatal zinc finger protein (ZFP) repression of mutant Huntingtin (HTT) in the zQ175DN knock-in mouse model of Huntington's disease (bulk RNA-seq)

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