Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function.
Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function.
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DOI：
10.1093/hmg/ddac105
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发表时间：
2022-09-10
影响因子：
3.5
通讯作者：
中科院分区：
文献类型：
--
作者：
精神分裂症的大规模基因组研究涉及通过组蛋白甲基化对转录进行表观遗传调控的基因和编码突触成分的基因。然而，这些途径之间的相互作用在赋予精神疾病的风险是未知的。编码组蛋白甲基转移酶（SETD1A）的基因中的功能丧失（LoF）突变赋予精神分裂症的重大风险。在几个角色中，SETD1A被认为参与神经元回路的发育和功能。在这里，我们采用了多组学的方法来研究杂合子Setd1a LoF对小鼠大脑皮层基因表达和突触组成的影响，从胚胎第14天到出生后第70天的5个发育时间点。使用RNA测序，我们观察到Setd1a LoF导致富含线粒体途径的基因的一致下调。这种效应延伸到突触体，我们发现线粒体和突触蛋白的年龄特异性破坏。使用大规模的患者基因组学数据，我们观察到差异表达的转录本或蛋白质中没有富集与精神分裂症的遗传关联，这表明它们来自基因组研究所涉及的不同风险机制。这项研究强调了SETD1A LOF可能导致精神分裂症风险的生物学途径。需要进一步的工作来确定在该模型中观察到的影响是否反映了人类病理学。
Large-scale genomic studies of schizophrenia implicate genes involved in the epigenetic regulation of transcription by histone methylation and genes encoding components of the synapse. However, the interactions between these pathways in conferring risk to psychiatric illness are unknown. Loss-of-function (LoF) mutations in the gene encoding histone methyltransferase, SETD1A, confer substantial risk to schizophrenia. Among several roles, SETD1A is thought to be involved in the development and function of neuronal circuits. Here, we employed a multi-omics approach to study the effects of heterozygous Setd1a LoF on gene expression and synaptic composition in mouse cortex across five developmental timepoints from embryonic day 14 to postnatal day 70. Using RNA sequencing, we observed that Setd1a LoF resulted in the consistent downregulation of genes enriched for mitochondrial pathways. This effect extended to the synaptosome, in which we found age-specific disruption to both mitochondrial and synaptic proteins. Using large-scale patient genomics data, we observed no enrichment for genetic association with schizophrenia within differentially expressed transcripts or proteins, suggesting they derive from a distinct mechanism of risk from that implicated by genomic studies. This study highlights biological pathways through which SETD1A LOF may confer risk to schizophrenia. Further work is required to determine whether the effects observed in this model reflect human pathology.
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影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
11
作者：
Clifton NE;Rees E;Holmans PA;Pardiñas AF;Harwood JC;Di Florio A;Kirov G;Walters JTR;O'Donovan MC;Owen MJ;Hall J;Pocklington AJ
通讯作者：
Pocklington AJ
影响因子：
3.7
作者：
Ben-Shachar, Dorit;Karry, Rachel
通讯作者：
Karry, Rachel
DOI：
10.1159/000441252
发表时间：
2015-12
期刊：
Molecular neuropsychiatry
影响因子：
--
作者：
Hjelm BE;Rollins B;Mamdani F;Lauterborn JC;Kirov G;Lynch G;Gall CM;Sequeira A;Vawter MP
通讯作者：
Vawter MP
DOI：
10.1038/ejhg.2015.218
发表时间：
2016-06
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
Ambalavanan A;Girard SL;Ahn K;Zhou S;Dionne-Laporte A;Spiegelman D;Bourassa CV;Gauthier J;Hamdan FF;Xiong L;Dion PA;Joober R;Rapoport J;Rouleau GA
通讯作者：
Rouleau GA