Nde1 is required for heterochromatin compaction and stability in neocortical neurons

Alison A. Chomiak, Yan Guo, Caroline A. Kopsidas, Dennis P. McDaniel, Clara C. Lowe, Hongna Pan, Xiaoming Zhou, Qiong Zhou, Martin L. Doughty, Yuanyi Feng*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The NDE1 gene encodes a scaffold protein essential for brain development. Although biallelic NDE1 loss of function (LOF) causes microcephaly with profound mental retardation, NDE1 missense mutations and copy number variations are associated with multiple neuropsychiatric disorders. However, the etiology of the diverse phenotypes resulting from NDE1 aberrations remains elusive. Here we demonstrate Nde1 controls neurogenesis through facilitating H4K20 trimethylation-mediated heterochromatin compaction. This mechanism patterns diverse chromatin landscapes and stabilizes constitutive heterochromatin of neocortical neurons. We demonstrate that NDE1 can undergo dynamic liquid-liquid phase separation, partitioning to the nucleus and interacting with pericentromeric and centromeric satellite repeats. Nde1 LOF results in nuclear architecture aberrations and DNA double-strand breaks, as well as instability and derepression of pericentromeric satellite repeats in neocortical neurons. These findings uncover a pivotal role of NDE1/Nde1 in establishing and protecting neuronal heterochromatin. They suggest that heterochromatin instability predisposes a wide range of brain dysfunction.

Original languageEnglish
Article number104354
JournaliScience
Volume25
Issue number6
DOIs
StatePublished - 17 Jun 2022
Externally publishedYes

Keywords

  • Biological sciences
  • Molecular biology
  • Neuroscience

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