SATB2 organizes the 3D genome architecture of cognition in cortical neurons

Mol Cell. 2024 Feb 15;84(4):621-639.e9. doi: 10.1016/j.molcel.2023.12.024. Epub 2024 Jan 19.

Abstract

The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.

Keywords: 3D genome; SATB2; chromatin accessibility; chromatin interactions; cognition; cortical neuron; epigenetics; neuronal genes; neuropsychiatric risk.

MeSH terms

  • CCCTC-Binding Factor / metabolism
  • Chromatin / genetics
  • Chromatin / metabolism
  • Cognition
  • Genome
  • Humans
  • Matrix Attachment Region Binding Proteins* / genetics
  • Matrix Attachment Region Binding Proteins* / metabolism
  • Neurons / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism

Substances

  • Transcription Factors
  • CCCTC-Binding Factor
  • Chromatin
  • SATB2 protein, human
  • Matrix Attachment Region Binding Proteins