Mapping brain gene coexpression in daytime transcriptomes unveils diurnal molecular networks and deciphers perturbation gene signatures

Nan Wang; Peter Langfelder; Matthew Stricos; Lalini Ramanathan; Jeffrey B Richman; Raymond Vaca; Mary Plascencia; Xiaofeng Gu; Shasha Zhang; T Katherine Tamai; Liguo Zhang; Fuying Gao; Koliane Ouk; Xiang Lu; Leonid V Ivanov; Thomas F Vogt; Qing Richard Lu; A Jennifer Morton; Christopher S Colwell; Jeffrey S Aaronson; Jim Rosinski; Steve Horvath; X William Yang

doi:10.1016/j.neuron.2022.09.028

Mapping brain gene coexpression in daytime transcriptomes unveils diurnal molecular networks and deciphers perturbation gene signatures

Neuron. 2022 Oct 19;110(20):3318-3338.e9. doi: 10.1016/j.neuron.2022.09.028.

Authors

Nan Wang¹, Peter Langfelder¹, Matthew Stricos¹, Lalini Ramanathan¹, Jeffrey B Richman¹, Raymond Vaca¹, Mary Plascencia¹, Xiaofeng Gu¹, Shasha Zhang¹, T Katherine Tamai², Liguo Zhang³, Fuying Gao⁴, Koliane Ouk⁵, Xiang Lu⁴, Leonid V Ivanov⁶, Thomas F Vogt⁷, Qing Richard Lu³, A Jennifer Morton⁵, Christopher S Colwell², Jeffrey S Aaronson⁷, Jim Rosinski⁷, Steve Horvath⁸, X William Yang⁹

Affiliations

¹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; UCLA Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁴ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
⁵ Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
⁶ Rancho Biosciences LLC, San Diego, CA, USA.
⁷ CHDI Management /CHDI Foundation, Princeton, NJ, USA.
⁸ Department of Human Genetics, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA, USA.
⁹ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: xwyang@mednet.ucla.edu.

Abstract

Brain tissue transcriptomes may be organized into gene coexpression networks, but their underlying biological drivers remain incompletely understood. Here, we undertook a large-scale transcriptomic study using 508 wild-type mouse striatal tissue samples dissected exclusively in the afternoons to define 38 highly reproducible gene coexpression modules. We found that 13 and 11 modules are enriched in cell-type and molecular complex markers, respectively. Importantly, 18 modules are highly enriched in daily rhythmically expressed genes that peak or trough with distinct temporal kinetics, revealing the underlying biology of striatal diurnal gene networks. Moreover, the diurnal coexpression networks are a dominant feature of daytime transcriptomes in the mouse cortex. We next employed the striatal coexpression modules to decipher the striatal transcriptomic signatures from Huntington's disease models and heterozygous null mice for 52 genes, uncovering novel functions for Prkcq and Kdm4b in oligodendrocyte differentiation and bipolar disorder-associated Trank1 in regulating anxiety-like behaviors and nocturnal locomotion.

Keywords: Huntington’s disease; Parkinson’s disease; Trank1; WGCNA; bipolar disorder; coexpression; cortex; diurnal; gene; striatum.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain
Gene Regulatory Networks
Huntington Disease* / genetics
Mice
Protein Kinase C-theta / genetics
Transcriptome*

Substances

Protein Kinase C-theta

Abstract

Publication types

MeSH terms

Substances

Grants and funding