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Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability

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 i...

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Autores principales: Cera, Isabella, Whitton, Laura, Donohoe, Gary, Morris, Derek W., Dechant, Georg, Apostolova, Galina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364870/
https://www.ncbi.nlm.nih.gov/pubmed/30726206
http://dx.doi.org/10.1371/journal.pgen.1007890
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author Cera, Isabella
Whitton, Laura
Donohoe, Gary
Morris, Derek W.
Dechant, Georg
Apostolova, Galina
author_facet Cera, Isabella
Whitton, Laura
Donohoe, Gary
Morris, Derek W.
Dechant, Georg
Apostolova, Galina
author_sort Cera, Isabella
collection PubMed
description 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.
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spelling pubmed-63648702019-02-22 Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability Cera, Isabella Whitton, Laura Donohoe, Gary Morris, Derek W. Dechant, Georg Apostolova, Galina PLoS Genet Research Article 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. Public Library of Science 2019-02-06 /pmc/articles/PMC6364870/ /pubmed/30726206 http://dx.doi.org/10.1371/journal.pgen.1007890 Text en © 2019 Cera et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Cera, Isabella
Whitton, Laura
Donohoe, Gary
Morris, Derek W.
Dechant, Georg
Apostolova, Galina
Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title_full Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title_fullStr Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title_full_unstemmed Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title_short Genes encoding SATB2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
title_sort genes encoding satb2-interacting proteins in adult cerebral cortex contribute to human cognitive ability
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364870/
https://www.ncbi.nlm.nih.gov/pubmed/30726206
http://dx.doi.org/10.1371/journal.pgen.1007890
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