@article{ae20413907ca4390ba8fa2a2a62fa3f6,
title = "Novel transcriptional networks regulated by clock in human neurons",
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.",
keywords = "Circadian rhythms, Evolution, Human brain, Neurogenomics, Neuronal migration",
author = "Fontenot, {Miles R.} and Stefano Berto and Yuxiang Liu and Gordon Werthmann and Connor Douglas and Noriyoshi Usu and Kelly Gleason and Tamminga, {Carol A.} and Takahashi, {Joseph S.} and Genevieve Konopka",
note = "Funding Information: We thank Dr. Victora Acosta and Dr. Noheon Park for help with ChIP optimization, Dr. Yongli Shan for assisting with luciferase experiments and analysis, and Dr. Guocun Huang for providing a 3xFlag-3xHA-tagged mouse CLOCK construct. We also thank the University of Texas Southwestern Neuroscience Imaging Core for allowing us to use their imaging equipment for the neu-rosphere experiments. Finally, thanks to all members of the Konopka laboratory for experimental help and support throughout this project. This work was supported by grants from the National Institute of Mental Health to G.K. (MH207672 and MH103517) and M.R.F. (MH105158), and the James S. McDon-nell Foundation 21st Century Science Initiative in Understanding Human Cognition-Scholar Award to G.K. G.K. is a Jon Heighten Scholar in Autism Research at University of Texas Southwestern. J.S.T. is an Investigator in the Howard Hughes Medical Institute. N.U. is a Research Fellow of the Uehara Memorial Foundation. M.R.F., S.B., J.S.T., and G.K. designed the experiments. M.R.F. performed all wet bench experiments, including all ChIP-seq, RNA-seq, ATAC-seq, and neurosphere migration assays. S.B. provided data analysis for all sequencing data. Y.L. carried out additional neurosphere and transwell assays with assistance from C.D. G.W. created CLOCK knockout 293T cells and performed CLOCK ChIP in these cells. N.U. provided experimental assis- tance. K.G. and C.A.T. provided human brain tissue for ChIP-seq experiments. G.K. conceived the study, and G.K. and J.S.T. supervised the study. M.R.F., S.B., J.S.T., and G.K. wrote the manuscript. All authors read and approved the final manuscript. Publisher Copyright: {\textcopyright} 2017 Fontenot et al.; Published by Cold Spring Harbor Laboratory Press.",
year = "2017",
month = nov,
day = "1",
doi = "10.1101/gad.305813.117",
language = "English (US)",
volume = "31",
pages = "2121--2135",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "21",
}