Institute for Neuroscience, Medical University of Innsbruck, Innsbruck, Austria.
Cognitive Genetics and Cognitive Therapy Group, Neuroimaging, Cognition and Genomics (NICOG) Centre and NCBES Galway Neuroscience Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland.
PLoS Genet. 2019 Feb 6;15(2):e1007890. doi: 10.1371/journal.pgen.1007890. eCollection 2019 Feb.
During CNS development, the nuclear protein SATB2 is expressed in superficial cortical layers and determines projection neuron identity. In the adult CNS, SATB2 is expressed in pyramidal neurons of all cortical layers and is a regulator of synaptic plasticity and long-term memory. Common variation in SATB2 locus confers risk of schizophrenia, whereas rare, de novo structural and single nucleotide variants cause severe intellectual disability and absent or limited speech. To characterize differences in SATB2 molecular function in developing vs adult neocortex, we isolated SATB2 protein interactomes at the two ontogenetic stages and identified multiple novel SATB2 interactors. SATB2 interactomes are highly enriched for proteins that stabilize de novo chromatin loops. The comparison between the neonatal and adult SATB2 protein complexes indicates a developmental shift in SATB2 molecular function, from transcriptional repression towards organization of chromosomal superstructure. Accordingly, gene sets regulated by SATB2 in the neocortex of neonatal and adult mice show limited overlap. Genes encoding SATB2 protein interactors were grouped for gene set analysis of human GWAS data. Common variants associated with human cognitive ability are enriched within the genes encoding adult but not neonatal SATB2 interactors. Our data support a shift in the function of SATB2 in cortex over lifetime and indicate that regulation of spatial chromatin architecture by the SATB2 interactome contributes to cognitive function in the general population.
在中枢神经系统（CNS）发育过程中，核蛋白 SATB2 在皮质表层表达，并决定投射神经元的身份。在成人 CNS 中，SATB2 表达于所有皮质层的锥体神经元，是突触可塑性和长期记忆的调节因子。SATB2 基因座的常见变异会增加精神分裂症的风险，而罕见的、新生的结构和单核苷酸变异会导致严重的智力障碍、言语缺失或受限。为了研究 SATB2 在发育中和成人新皮质中的分子功能差异，我们在这两个发育阶段分离了 SATB2 蛋白相互作用组，并鉴定了多个新的 SATB2 相互作用因子。SATB2 相互作用组富含稳定新生染色质环的蛋白。新生儿和成年 SATB2 蛋白复合物之间的比较表明，SATB2 的分子功能发生了发育性转变，从转录抑制转向染色体超结构的组织。相应地，SATB2 在新生和成年小鼠新皮质中调节的基因集显示出有限的重叠。SATB2 蛋白相互作用因子的编码基因被分组进行人类 GWAS 数据的基因集分析。与人类认知能力相关的常见变异在编码成年而非新生 SATB2 相互作用因子的基因中富集。我们的数据支持 SATB2 在整个生命过程中皮层功能的转变，并表明 SATB2 相互作用组对空间染色质结构的调节有助于普通人群的认知功能。
