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| Status |
Public on May 08, 2024 |
| Title |
Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia |
| Platform organism |
Homo sapiens |
| Sample organisms |
Homo sapiens; Rattus norvegicus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
Third-party reanalysis
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| Summary |
Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ.
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| Overall design |
ChIP-seq of TCF7L2 and OLIG2 in human GPCs and HepG2; ChIP-seq of Tcf7l2 in rat glial cells
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| Contributor(s) |
Huynh NP, Osipovitch M, Foti R, Bates J, Mansky B, Cano JC, Benraiss A, Zhao C, Lu Q, Goldman SA |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Nov 10, 2021 |
| Last update date |
May 09, 2024 |
| Contact name |
Steven Goldman |
| Organization name |
University of Rochester Medical Center
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| Department |
Center for Translational Neuromedicine
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| Lab |
Goldman Lab
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| Street address |
601 Elmwood Ave
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| City |
Rochester |
| State/province |
NY |
| ZIP/Postal code |
14642 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE188561 |
Shared patterns of glial transcriptional dysregulation link Huntington's disease and schizophrenia |
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| Relations |
| Reanalysis of |
GSM782122 |
| Reanalysis of |
GSM1587566 |
| Reanalysis of |
GSM1587567 |
| Reanalysis of |
GSM1587568 |
| BioProject |
PRJNA779420 |
| SRA |
SRP345435 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE188559_HepG2_TCF7L2_treat_pileup.bw |
263.8 Mb |
(ftp)(http) |
BW |
| GSE188559_RAW.tar |
242.1 Mb |
(http)(custom) |
TAR (of BW, NARROWPEAK) |
| GSE188559_TCF7L2_HepG2_peaks.narrowPeak.gz |
56.0 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE188559_Tcf7l2_OPC_peaks.narrowPeak.gz |
54.5 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE188559_Tcf7l2_OPC_treat_pileup.bw |
275.7 Mb |
(ftp)(http) |
BW |
| GSE188559_Tcf7l2_iOL_peaks.narrowPeak.gz |
599.0 Kb |
(ftp)(http) |
NARROWPEAK |
| GSE188559_Tcf7l2_iOL_treat_pileup.bw |
93.8 Mb |
(ftp)(http) |
BW |
| GSE188559_Tcf7l2_mOL_peaks.narrowPeak.gz |
2.1 Mb |
(ftp)(http) |
NARROWPEAK |
| GSE188559_Tcf7l2_mOL_treat_pileup.bw |
318.8 Mb |
(ftp)(http) |
BW |
| GSE188559_readme.txt |
401 b |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
| Processed data provided as supplementary file |
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