Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers

Tiziano Pramparo, Michael V. Lombardo, Kathleen Campbell, Cynthia Carter Barnes, Steven Marinero, Stephanie Solso, Julia Young, Maisi Mayo, Anders Dale, Clelia Ahrens-Barbeau, Sarah S. Murray, Linda Lopez, Nathan Lewis, Karen Pierce, Eric Courchesne

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi-tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
Original languageEnglish
Article number841
JournalMolecular Systems Biology
Volume11
Issue number12
Number of pages18
ISSN1744-4292
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Autism Spectrum Disorder
  • Brain development
  • Co‐expression
  • Gene networks

Fingerprint Dive into the research topics of 'Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers'. Together they form a unique fingerprint.

Cite this