Druggable Transcriptional Networks in the Human Neurogenic Epigenome

Abstract

Chromosome conformation capture methods have revealed the dynamics of genome architecture which is spatially organized into topologically associated domains, with gene regulation mediated by enhancer-promoter pairs in chromatin space. New evidence shows that endogenous hormones and several xenobiotics act within circumscribed topological domains of the spatial genome, impacting subsets of the chromatin contacts of enhancer-gene promoter pairs in cis and trans. Results from the National Institutes of Health-funded PsychENCODE project and the study of chromatin remodeling complexes have converged to provide a clearer understanding of the organization of the neurogenic epigenome in humans. Neuropsychiatric diseases, including schizophrenia, bipolar spectrum disorder,

Anticonvulsants and Chromatin-Genes Expression: A Systems Biology Investigation

“…SMARCA-deficiencies are associated to several malignancies and birth defects; its homozygous loss lead to embryo lethality (Pulice and Kadoch, 2016). Valproic acid is known to alter the expression of SMARCA4 and SMARCD1 in neuroblastoma cells (Hu et al, 2020), and SMARCA genes are suggested as members of the neurogenic transcriptional network control (Higgins et al, 2019). Hence, valproate-induced perturbances in SMARCA genes might be sufficiently disruptive to explain Fetal Valproate Syndrome.…”

Ketamine’s pharmacogenomic network in human brain contains sub-networks associated with glutamate neurotransmission and with neuroplasticity

“…This research emphasizes the role of the regulatory genome, including enhancer and superenhancer-based interactomes, as an approach that provides insight into pharmacogenomic network mechanisms (22)(23)(24)(25). It differs from pathway modeling methods in which altered protein folding based on missense codon variants and fixed signaling pathways serve as the foundation for the interpretation of the molecular substrate of ketamine response in humans.…”

“…The ketamine response workflow is based on the pharmacoepigenomics informatics pipeline (PIP) (22)(23)(24)(25). Input genes to the data analysis pipeline first included those genes that encode proteins and constituents of macromolecular protein complexes obtained from past studies of the binding affinity of (R, S)-ketamine, R-ketamine and S-ketamine performed in microsomal and tissue preparations in rodents and humans.…”

“…Our pharmaco-informatics platform processes data with minimal human intervention to avoid inhouse bias. Human SNPs were selected and processed using a revised version of the bioinformatics pipeline that has been described in detail in previous publications (22)(23)(24)(25). For the workflow used in this study, GWAS SNPs were used as reported.…”

“…Our strategy analyzed disparate data from multiple scales of biological function combining bioinformatics, computational medicine and machine learning (22)(23)(24)(25). GWAS SNPs provided insight into the phenotypic consequences of the mutational alterations and variation within disease sub-networks impacted by ketamine, spatial interactions within chromatin that control expression of ketamine-response genes, and mesoscale functional neurocircuits within human brain regions that are rapidly activated following ketamine administration (Figure 1).…”