Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex

Nicole Büttner, Steven A. Johnsen, Sebastian Kügler, Tanja Vogel

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia, but little is known about how AF9 influences brain development and function. Analyses of mouse mutants revealed that during cortical development, AF9 is involved in the maintenance of TBR2-positive progenitors (intermediate precursor cells, IPCs) in the subventricular zone and prevents premature cell cycle exit of IPCs. Furthermore, in post-mitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons.We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a protein that mediates transcriptional control through methylation of histone H3 lysine 79 (H3K79). AF9 associates with the transcriptional start site of Tbr1, mediates H3K79 dimethylation of the Tbr1 gene, and interferes with the presence of RNA polymerase II at the Tbr1 transcriptional start site. AF9 expression favors cytoplasmic localization of TBR1 and its association with mitochondria. Increased expression of TBR1 in Af9 mutants is associated with increased levels of TBR1-regulated expression of NMDAR subunit Nr1. Thus, this study identified AF9 as a developmental active epigenetic modifier during the generation of cortical projection neurons.

Original languageEnglish (US)
Pages (from-to)7042-7047
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number15
DOIs
StatePublished - Apr 13 2010

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Keywords

  • Dot1l
  • Histone methylation
  • Nr1
  • Tbr2
  • Upper layer neurons

ASJC Scopus subject areas

  • General

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