DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex

Nucleic Acids Res. 2019 Jan 10;47(1):168-183. doi: 10.1093/nar/gky953.

Abstract

Cortical development is controlled by transcriptional programs, which are orchestrated by transcription factors. Yet, stable inheritance of spatio-temporal activity of factors influencing cell fate and localization in different layers is only partly understood. Here we find that deletion of Dot1l in the murine telencephalon leads to cortical layering defects, indicating DOT1L activity and chromatin methylation at H3K79 impact on the cell cycle, and influence transcriptional programs conferring upper layer identity in early progenitors. Specifically, DOT1L prevents premature differentiation by increasing expression of genes that regulate asymmetric cell division (Vangl2, Cenpj). Loss of DOT1L results in reduced numbers of progenitors expressing genes including SoxB1 gene family members. Loss of DOT1L also leads to altered cortical distribution of deep layer neurons that express either TBR1, CTIP2 or SOX5, and less activation of transcriptional programs that are characteristic for upper layer neurons (Satb2, Pou3f3, Cux2, SoxC family members). Data from three different mouse models suggest that DOT1L balances transcriptional programs necessary for proper neuronal composition and distribution in the six cortical layers. Furthermore, because loss of DOT1L in the pre-neurogenic phase of development impairs specifically generation of SATB2-expressing upper layer neurons, our data suggest that DOT1L primes upper layer identity in cortical progenitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Division / genetics
  • Cell Proliferation / genetics
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism
  • Chromatin / genetics
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation, Developmental
  • Histone-Lysine N-Methyltransferase
  • Matrix Attachment Region Binding Proteins / genetics*
  • Methylation
  • Methyltransferases / genetics*
  • Mice
  • Neurogenesis / genetics*
  • Neurons / metabolism*
  • Neurons / pathology
  • Repressor Proteins / genetics
  • SOXD Transcription Factors / genetics
  • T-Box Domain Proteins
  • Telencephalon / growth & development
  • Telencephalon / metabolism
  • Telencephalon / pathology
  • Transcription Factors / genetics*
  • Tumor Suppressor Proteins / genetics

Substances

  • Bcl11b protein, mouse
  • Chromatin
  • DNA-Binding Proteins
  • Matrix Attachment Region Binding Proteins
  • Repressor Proteins
  • SATB2 protein, mouse
  • SOXD Transcription Factors
  • Sox5 protein, mouse
  • T-Box Domain Proteins
  • Tbr1 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Dot1l protein, mouse
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase