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Series GSE148440 Query DataSets for GSE148440
Status Public on Jun 01, 2020
Title Molecular and cellular consequences of genetic knockout of Hdac2 and Hdac3 in striatal medium spiny neurons of Huntington's disease knock-in mice
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process resulting in neuronal cell death. Although mechanisms of neuronal toxicity are not well delineated, transcriptional dysregulation is a likely contributor. Chromatin modifiers are implicated in both mechanisms of CAG instability and transcriptional dysregulation. Here, we tested whether histone deacetylase genes Hdac2 and Hdac3 modify molecular and cellular phenotypes in HttQ111 knock-in mice using conditional knockouts in striatal medium-spiny striatal neurons (MSNs) exhibiting extensive CAG expansion and exquisite disease vulnerability. MSN-specific Hdac2 or Hdac3 knockout attenuated CAG expansion, with the Hdac2 knockout impacting nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included reversal of transcriptional dysregulation elicited by the HttQ111 allele. Our results identify novel modifiers of CAG expansion in MSNs, providing testable mechanistic hypotheses, and a potentially complex relationship between Htt and Hdac2 with implications for targeting transcriptional dysregulation in HD.
Overall design RNA sequencing in 35 mouse striatal tissues of four genotype groups: HttQ111/+ Hdac2+/+ , Htt+/+ Hdac2+/+ , HttQ111/+ Hdac2D/D , Htt+/+ Hdac2D/D
Contributor(s) Kovalenko M, Erdin S, Andrew MA, St. Claire J, Shaughnessey M, Hubert L, Neto JL, Stortchevoi A, Fass DM, Pinto RM, Haggarty SJ, Wilson JH, Talkowski ME, Wheeler VC
Citation(s) 32990597
Submission date Apr 10, 2020
Last update date Oct 27, 2020
Contact name Serkan Erdin
Organization name Massachusetts General Hospital
Department Center for Genomic Medicine
Lab Talkowski Lab
Street address 185 Cambridge Street
City Boston
State/province MA
ZIP/Postal code 02114
Country USA
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (35)
GSM4471489 1C_A5445: HttQ111/+ Hdac2+/+ rep1
GSM4471490 1F_A5783: HttQ111/+ Hdac2+/+ rep2
GSM4471491 2E_V1347: HttQ111/+ Hdac2+/+ rep3
BioProject PRJNA624273
SRA SRP255943

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Supplementary file Size Download File type/resource
GSE148440_countdata.csv.gz 2.0 Mb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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