HIV Tat and cocaine interactively alter genome-wide DNA methylation and gene expression and exacerbate learning and memory impairments
Xiaojie Zhao,
Fan Zhang,
Suresh R. Kandel,
Frédéric Brau,
Johnny J. He
Affiliations
Xiaojie Zhao
Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University, North Chicago, IL 60064, USA; Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA; School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL 60064, USA
Fan Zhang
Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA
Suresh R. Kandel
Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University, North Chicago, IL 60064, USA; Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA
Frédéric Brau
Université Côte d’Azur, CNRS, IPMC, Sophia-Antipolis 06560, France
Johnny J. He
Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University, North Chicago, IL 60064, USA; Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA; School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL 60064, USA; Corresponding author
Summary: Cocaine use is a major comorbidity of HIV-associated neurocognitive disorder (HAND). In this study, we show that cocaine exposure worsens the learning and memory of doxycycline-inducible and brain-specific HIV Tat transgenic mice (iTat) and results in 14,838 hypermethylated CpG-related differentially methylated regions (DMRs) and 15,800 hypomethylated CpG-related DMRs, which are linked to 52 down- and 127 upregulated genes, respectively, in the hippocampus of iTat mice. These genes are mostly enriched at the neuronal function-, cell morphology-, and synapse formation-related extracellular matrix (ECM) receptor-ligand interaction pathway and mostly impacted in microglia. The accompanying neuropathological changes include swollen dendritic spines, increased synaptophysin expression, and diminished glial activation. We also find that sex (female) and age additively worsen the behavioral and pathological changes. These findings together indicate that chronic cocaine and long-term Tat expression interactively contribute to HAND, likely involving changes of DNA methylation and ECM receptor-ligand interactions.
