HESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA414457 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6178390_1.fastq.gz | Fastqsanger.gz | |||
| SRR6178390_2.fastq.gz | Fastqsanger.gz | |||
| SRR6178400.fastq.gz | Fastqsanger.gz | |||
| SRR6178410.fastq.gz | Fastqsanger.gz | |||
| SRR6178391_1.fastq.gz | Fastqsanger.gz |
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Project description:Huntington’s disease (HD) is characterized by hypomyelination as well as by neuronal loss. To assess the basis for white matter involution in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs), derived from either huntingtin (mHTT)-mutant embryos or normal controls, and performed RNA sequence analysis to assess mHTT-dependent changes in gene expression. In hGPCs derived from 3 distinct mHTT-expressing hESC lines, a set of transcription factors associated with glial differentiation and myelin synthesis was sharply down-regulated, relative to normal hESC GPCs. In particular, NKX2.2, OLIG2, SOX10 and MYRF were all suppressed, with the consequent diminution of myelinogenesis-associated transcription. Accordingly, when mHTT-expressing hGPCs were transplanted into hypomyelinated shiverer mice, the resultant mHTT glial chimeras were hypomyelinated. The mHTT hGPCs also manifested impaired astrocytic differentiation, and developed abnormal fiber domain architecture. These data suggest that white matter involution in HD is a product of a cell-autonomous mHTT-dependent suppression of both astrocytic and oligodendrocytic differentiation by affected GPCs.
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Project description:Whole proteome profiling and quantification was performed on an isogenic Huntington disease (IsoHD) human embryonic stem cell (hESC) allelic panel. The IsoHD hESCs harbour 30, 45, 65 and 81 CAG repeats in the first exon of HTT. Whole proteome quantification was also performed on neural progenitor cells derived from the IsoHD hESC panel.
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