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| Status |
Public on Oct 09, 2019 |
| Title |
Recapitulation and reversal of schizophrenia-related phenotypes in Setd1a-deficient mice |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
SETD1A, a histone methyltransferase, is a key schizophrenia susceptibility gene. Mutant mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics, accompanied by specific deficits in working memory that recapitulates SCZ-related alterations. We show that Setd1a targets mostly enhancers and reveal a striking overlap between Setd1a and Mef2 chromatin targets. Setd1a targets are highly expressed in pyramidal neurons and enriched for genes with postnatally-biased expression involved in synaptic structure and function. Notably, evolutionary conserved Setd1a binding sites and target genes are strongly associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues working memory deficits. We identify LSD1 as a major demethylase counteracting the effects of Setd1a methyl transferase activity and show that LSD1 antagonism in adult Setd1a-deficient mice results in a full rescue of the behavioral abnormalities and axonal branching deficits. Our findings advance our understanding of how SETD1A mutations predispose to SCZ and point to therapeutic interventions.
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| |
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| Overall design |
Setd1a-deficient mice
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| |
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| Contributor(s) |
Gogos J, Lomvardas S, Mukai J, Cannavo E |
| Citation(s) |
35680927 |
| Submission date |
Dec 11, 2018 |
| Last update date |
Jun 24, 2022 |
| Contact name |
Joseph Gogos |
| E-mail(s) |
jag90@columbia.edu
|
| Phone |
9177426412
|
| Organization name |
Columbia University
|
| Street address |
3227 Broadway, JGL Science Bldg, Quad 4A, Room L4-005
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10027 |
| Country |
USA |
| |
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| Platforms (2) |
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| Samples (32)
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| Relations |
| BioProject |
PRJNA509455 |
| SRA |
SRP173306 |
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