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Review ArticleReview Article

Druggable Transcriptional Networks in the Human Neurogenic Epigenome

Gerald A. Higgins, Aaron M. Williams, Alex S. Ade, Hasan B. Alam and Brian D. Athey
Lori L. Isom, ASSOCIATE EDITOR
Pharmacological Reviews October 2019, 71 (4) 520-538; DOI: https://doi.org/10.1124/pr.119.017681
Gerald A. Higgins
Departments of Computational Medicine and Bioinformatics (G.A.H., A.S.A., B.D.A.), Surgery (A.M.W., H.B.A.), and Psychiatry (B.D.A.), University of Michigan Medical School, Ann Arbor, Michigan
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Aaron M. Williams
Departments of Computational Medicine and Bioinformatics (G.A.H., A.S.A., B.D.A.), Surgery (A.M.W., H.B.A.), and Psychiatry (B.D.A.), University of Michigan Medical School, Ann Arbor, Michigan
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Alex S. Ade
Departments of Computational Medicine and Bioinformatics (G.A.H., A.S.A., B.D.A.), Surgery (A.M.W., H.B.A.), and Psychiatry (B.D.A.), University of Michigan Medical School, Ann Arbor, Michigan
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Hasan B. Alam
Departments of Computational Medicine and Bioinformatics (G.A.H., A.S.A., B.D.A.), Surgery (A.M.W., H.B.A.), and Psychiatry (B.D.A.), University of Michigan Medical School, Ann Arbor, Michigan
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Brian D. Athey
Departments of Computational Medicine and Bioinformatics (G.A.H., A.S.A., B.D.A.), Surgery (A.M.W., H.B.A.), and Psychiatry (B.D.A.), University of Michigan Medical School, Ann Arbor, Michigan
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Lori L. Isom
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    The noncoding regulatory genome, causal SNPs and chromatin state. (A) Pharmacogenomic SNPs associated with drug response or adverse drug events from GWAS are predominately located within enhancers (81%), and only 4% are called as exonic missense variants that could putatively disrupt protein structure or protein-protein interactions. (B) Illustration of genomic DNA, which is packaged within chromatin, and the different attributes of causal SNPs from GWAS that act on the epigenome. (C) Histone modifications significantly associated with enhancers, promoters, euchromatin, and heterochromatin the human genome.

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    Fig. 2.

    Characteristics and distribution of human TADs. (A) Data-driven analysis of TADs, enhancers, protein-coding genes, and TADs boundaries in the H1 neuronal human cell line. (B) Human gene classes most significantly associated with super-enhancers in embryonic stem cells.

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    Fig. 3.

    Drugs act to differentially activate and suppress circumscribed sets of TADs concomitant with differential gene expression through alteration of the geometry of the 3D genome. (A and B) Schematic depiction of two adjacent TADs, which are expanded driving differential gene expression following drug exposure. (C) Causal SNPs from GWAS are most found within noncoding enhancers, and their target gene promoter set is more likely to be within the same TAD.

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    Fig. 4.

    The npBAF and nBAF chromatin remodeling complexes: components and associated neurodevelopmental disorders. The criticality of these complexes in developmental gene regulation in neurons suggests that any mutation causes severe neurodevelopmental disorders. Modified in part from Ronan et al. (2013) and Sokpor et al. (2018). For gene names, please see Supplemental Table 1.

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    Fig. 5.

    Transcription factor and nuclear receptor genes identified in enhancer-promoter TAD loops within neurogenic transcriptional networks in studies from the PsychENCODE Consortium and related research. (A) Output from IPA (Krämer et al., 2013) of a highly interconnected pathway involved in neurologic development and disorders (P = 1 × 10E−130). (B) Top upstream chemical-drug regulators of the network shown in (A) as determined by IPA and KEGG (Kanehisa et al., 2016). (C) Top five human neurologic disorders significantly associated with neurogenic network. (D) Top five human nervous system biologic processes. (E) Top five molecular functions determined by Gene Ontology (The Gene Ontology Consortium, 2019). For gene names, please see Supplemental Table 2.

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    Fig. 6.

    Direct therapeutic approaches. (A) Synthetic construct containing the enhancer and promoters of the SMN1 gene, including inverted terminal repeats specific to the AAV vector being used in clinical trials for a one-time cure for pediatric spinal muscle atrophy. A similar approach may be used to modify regulatory RNAs that act as neurogenic transcriptional network controllers. ITR, inverted terminal repeats; Poly A, polyadenylated mRNA tail for translation. Modified from Novartis investor Presentation. 2018 (unpublished data). (B). strategy to de-repress the POU5F1 gene locus held constrained by PRC1 and PRC2 through the use of an antibiotic-inducible compound that specifically adds the BAF chromatin remodeling complex to the gene, allowing it to re-assume control of a pluripotent control network modified from Crabtree et al. (2018) and Young, (2011).

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Pharmacological Reviews: 71 (4)
Pharmacological Reviews
Vol. 71, Issue 4
1 Oct 2019
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Review ArticleReview Article

Drug Networks in the Regulatory Epigenome

Gerald A. Higgins, Aaron M. Williams, Alex S. Ade, Hasan B. Alam and Brian D. Athey
Pharmacological Reviews October 1, 2019, 71 (4) 520-538; DOI: https://doi.org/10.1124/pr.119.017681

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Review ArticleReview Article

Drug Networks in the Regulatory Epigenome

Gerald A. Higgins, Aaron M. Williams, Alex S. Ade, Hasan B. Alam and Brian D. Athey
Pharmacological Reviews October 1, 2019, 71 (4) 520-538; DOI: https://doi.org/10.1124/pr.119.017681
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