Novel transcriptional networks regulated by clock in human neurons

Miles R. Fontenot, Stefano Berto, Yuxiang Liu, Gordon Werthmann, Connor Douglas, Noriyoshi Usu, Kelly Gleason, Carol A. Tamminga, Joseph S. Takahashi, Genevieve Konopka

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function.

Original languageEnglish (US)
Pages (from-to)2121-2135
Number of pages15
JournalGenes and Development
Volume31
Issue number21
DOIs
StatePublished - Nov 1 2017

Keywords

  • Circadian rhythms
  • Evolution
  • Human brain
  • Neurogenomics
  • Neuronal migration

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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  • Cite this

    Fontenot, M. R., Berto, S., Liu, Y., Werthmann, G., Douglas, C., Usu, N., Gleason, K., Tamminga, C. A., Takahashi, J. S., & Konopka, G. (2017). Novel transcriptional networks regulated by clock in human neurons. Genes and Development, 31(21), 2121-2135. https://doi.org/10.1101/gad.305813.117