| First Author | Mukai J | Year | 2019 |
| Journal | Neuron | Volume | 104 |
| Issue | 3 | Pages | 471-487.e12 |
| PubMed ID | 31606247 | Mgi Jnum | J:282568 |
| Mgi Id | MGI:6381699 | Doi | 10.1016/j.neuron.2019.09.014 |
| Citation | Mukai J, et al. (2019) Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice. Neuron 104(3):471-487.e12 |
| abstractText | SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions. |
