SATB2-LEMD2 interaction links nuclear shape plasticity to regulation of cognition-related genes

EMBO J. 2021 Feb 1;40(3):e103701. doi: 10.15252/embj.2019103701. Epub 2020 Dec 15.

Abstract

SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes in nuclear shape of CA1 hippocampal neurons via a SATB2-dependent mechanism. The activity-driven plasticity of the nuclear envelope requires not only SATB2, but also its protein interactor LEMD2 and the ESCRT-III/VPS4 membrane-remodeling complex. Furthermore, LEMD2 depletion in cortical neurons, similar to SATB2 ablation, affects neuronal activity-dependent regulation of multiple rapid and delayed primary response genes. In human genetic data, LEMD2-regulated genes are enriched for de novo mutations reported in intellectual disability and schizophrenia and are, like SATB2-regulated genes, enriched for common variants associated with schizophrenia and cognitive function. Hence, interactions between SATB2 and the inner nuclear membrane protein LEMD2 influence gene expression programs in pyramidal neurons that are linked to cognitive ability and psychiatric disorder etiology.

Keywords: SATB2; chromatin; human cognitive ability; neuronal activity; nuclear envelope.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / metabolism
  • Animals
  • Cell Nucleus / metabolism
  • Cell Plasticity
  • Cells, Cultured
  • Cognition
  • Endosomal Sorting Complexes Required for Transport / metabolism
  • Gene Regulatory Networks*
  • HeLa Cells
  • Hippocampus / cytology*
  • Hippocampus / metabolism
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Male
  • Matrix Attachment Region Binding Proteins / chemistry
  • Matrix Attachment Region Binding Proteins / genetics
  • Matrix Attachment Region Binding Proteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mutation*
  • Neurons / cytology
  • Neurons / metabolism
  • Nuclear Envelope / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • Endosomal Sorting Complexes Required for Transport
  • LEMD2 protein, human
  • Matrix Attachment Region Binding Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • SATB2 protein, human
  • Transcription Factors
  • Vacuolar Proton-Translocating ATPases
  • ATPases Associated with Diverse Cellular Activities
  • VPS4A protein, human

Associated data

  • GEO/GSE157375