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The road to precision psychiatry: translating genetics into disease mechanisms
Gandal, Michael J,Leppa, Virpi,Won, Hyejung,Parikshak, Neelroop N,Geschwind, Daniel H NATURE AMERICA 2016 NATURE NEUROSCIENCE Vol.19 No.11
Hundreds of genetic loci increasing risk for neuropsychiatric disorders have recently been identified. This success, perhaps paradoxically, has posed challenges for therapeutic development, which are amplified by the highly polygenic and pleiotropic nature of these genetic contributions. Success requires understanding the biological impact of single genetic variants and predicting their effects within an individual. Comprehensive functional genomic annotation of risk loci provides a framework for interpretation of neurobiological impact, requiring experimental validation with in vivo or in vitro model systems. Systems-level, integrative pathway analyses are beginning to elucidate the additive, polygenic contributions of risk variants on specific cellular, molecular, developmental, or circuit-level processes. Although most neuropsychiatric disease modeling has focused on genes disrupted by rare, large-effect-size mutations, common smaller-effect-size variants may also provide solid therapeutic targets to inform precision medicine approaches. Here we enumerate the promise and challenges of a genomics-driven approach to uncovering neuropsychiatric disease mechanisms and facilitating therapeutic development.
Beyaz, Semir,Kim, Ji Hyung,Pinello, Luca,Xifaras, Michael E,Hu, Yu,Huang, Jialiang,Kerenyi, Marc A,Das, Partha P,Barnitz, R Anthony,Herault, Aurelie,Dogum, Rizkullah,Haining, W Nicholas,Yilmaz, Ö NATURE AMERICA INC 2017 NATURE IMMUNOLOGY Vol.18 No.2
Invariant natural killer T cells (iNKT cells) are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about the epigenetic regulation of iNKT cell development. Here we found that the H3K27me3 histone demethylase UTX was an essential cell-intrinsic factor that controlled an iNKT-cell lineage-specific gene-expression program and epigenetic landscape in a demethylase-activity-dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT cell signature genes due to a decrease in activation-associated H3K4me3 marks and an increase in repressive H3K27me3 marks within the promoters occupied by UTX. We found that JunB regulated iNKT cell development and that the expression of genes that were targets of both JunB and the iNKT cell master transcription factor PLZF was UTX dependent. We identified iNKT cell super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for commitment to the iNKT cell lineage. Our findings reveal how UTX regulates the development of iNKT cells through multiple epigenetic mechanisms.
Naik, Shalin H,Sathe, Priyanka,Park, Hae-Young,Metcalf, Donald,Proietto, Anna I,Dakic, Aleksander,Carotta, Sebastian,O'Keeffe, Meredith,Bahlo, Melanie,Papenfuss, Anthony,Kwak, Jong-Young,Wu, Li,Shortm NATURE AMERICA INC 2007 NATURE IMMUNOLOGY Vol.8 No.11
The development of functionally specialized subtypes of dendritic cells (DCs) can be modeled through the culture of bone marrow with the ligand for the cytokine receptor Flt3. Such cultures produce DCs resembling spleen plasmacytoid DCs (pDCs), CD8<SUP>+</SUP> conventional DCs (cDCs) and CD8<SUP>−</SUP> cDCs. Here we isolated two sequential DC-committed precursor cells from such cultures: dividing 'pro-DCs', which gave rise to transitional 'pre-DCs' en route to differentiating into the three distinct DC subtypes (pDCs, CD8<SUP>+</SUP> cDCs and CD8<SUP>−</SUP> cDCs). We also isolated an in vivo equivalent of the DC-committed pro-DC precursor cell, which also gave rise to the three DC subtypes. Clonal analysis of the progeny of individual pro-DC precursors demonstrated that some pro-DC precursors gave rise to all three DC subtypes, some produced cDCs but not pDCs, and some were fully committed to a single DC subtype. Thus, commitment to particular DC subtypes begins mainly at this pro-DC stage.
Determinants of residential indoor and transportation activity times in Korea
Yang, Wonho,Lee, Kiyoung,Yoon, Chungsik,Yu, Seungdo,Park, Kyunghwa,Choi, Wookhee Nature America, Inc. 2011 Journal of exposure science & environmental epidem Vol.21 No.3
Information on time spent in microenvironments has a critical role for personal exposure to environmental pollutants. Unlike several large-scale studies in Western countries, no comprehensive research on time-activity patterns for exposure assessment has been conducted in Korea. We investigated determinants of residential indoor and transportation times of individuals over 10-years old in the Korean population. The population-based study collected time-activity patterns of 31,634 Koreans for two consecutive days. The residential indoor and transportation times were collected for a weekday and a weekend day. The impact of sociodemographic factors on time-activity was assessed using multiple linear regression models. The residential indoor times were 14.23 h for the weekday and 16.13 h for the weekend and shorter than those in Western countries. The transportation times were 1.75 h for the weekday and 1.68 h for the weekend day. The most significant factors in residential indoor time were employment status, age, monthly income, and gender for the weekday and employment status and gender for the weekend day. The factors in transportation were gender, employment status, and monthly income for the weekday and gender, employment status, age, and marriage status for the weekend day. Determinants of the time-activity pattern need to be taken into account in exposure assessment, epidemiological analyses, and exposure simulations, as well as in the development of preventive strategies. As Korean population activity patterns are substantially different from those in Western countries such as USA, Germany, and UK, this information could be critical for exposure assessment in Korea and other Asian countries.
Malilas, W,Koh, S S,Srisuttee, R,Boonying, W,Cho, I-R,Jeong, C-S,Johnston, R N,Chung, Y-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.2
We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 2′–5′ oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis. Taken together, we propose that VSV treatment combined with the selective regulation of genes such as STAT1 and OASL2 will improve therapeutic outcomes for CUG2-overexpressing tumors.
Chang, S-H,Kim, J-E,Lee, J-H,Minai-Tehrani, A,Han, K,Chae, C,Cho, Y-H,Yun, J-H,Park, K,Kim, Y-S,Cho, M-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.6
Conventional radiotherapy or chemotherapy for the long-term survival of patients with lung cancer is still difficult for treatment in metastatic and advanced tumors. Therefore, the safe and effective approaches to the treatment of lung cancer are needed. In this study, the effect of delivered eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) on lung cancer progression was evaluated. Recombinant adeno-associated virus (rAAV)-M3/4E-BP1 was delivered into 6-week-old K-ras<SUP>LA1</SUP> lung cancer model mice through a nose-only inhalation system twice a week for 4 weeks. Long-term repeated delivery of 4E-BP1 effectively reduced tumor progression in the lungs of K-ras<SUP>LA1</SUP> mice. Reduction of eIF4E by overexpression of 4E-BP1 resulted in suppression of cap-dependent protein expression of basic fibroblast growth factor (bFGF or FGF-2) and vascular endothelial growth factor (VEGF). In addition, delivered 4E-BP1 inhibited the proliferation of lung cancer cells in K-ras<SUP>LA1</SUP> mice model. Our results suggest that long-term repeated viral delivery of 4E-BP1 may provide a useful tool for designing lung cancer treatment.
Shin, J-Y,Chung, Y-S,Kang, B,Jiang, H-L,Yu, D-Y,Han, K,Chae, C,Moon, J-H,Jang, G,Cho, M-H Nature America, Inc. 2013 Cancer gene therapy Vol.20 No.3
As hepatocellular carcinoma (HCC) is one of the most common tumors worldwide, development of novel therapeutic approaches for HCC is urgently needed. Two different genes, LETM1 and CTMP, which target mitochondrial functions, were chosen and linked using 2A-peptide sequence. Successful self-cleavage of 2A-peptide induced synergistic antitumor effect in the liver of H-ras12V, the HCC model mice, by simultaneous activation of LETM1 (Leucine zipper/EF hand-containing transmembrane-1) and CTMP (carboxyl-terminal modulator protein). Overexpression of LETM1 and CTMP significantly reduced the incidence of tumorigenesis, which were confirmed by gross and microscopic observations. Morphological changes in mitochondria, such as swelling and loss of cristae, were significant, and the prolonged activation of defects in mitochondrial function led to mitochondria-mediated apoptosis. Furthermore, with CTMP as a direct binding partner of Akt1, and LETM1 as a binding partner of CTMP, LETM1-2A-CTMP downregulated the Akt1 pathway at both Ser473 and Thr308 sites of phosphorylation. Proliferation and angiogenesis, which are important in cancer prognosis, were reduced in tumor sites after introduction of LETM1-2A-CTMP. Taken together, the results indicate that introduction of the mitochondria-targeting genes, LETM1 and CTMP, and self-processing capacity of 2A-peptide sequence exerts an antitumor effect in liver of H-ras12V mice, suggesting its potential as a tool for gene therapy.
NGL family PSD-95–interacting adhesion molecules regulate excitatory synapse formation
Kim, Seho,Burette, Alain,Chung, Hye Sun,Kwon, Seok-Kyu,Woo, Jooyeon,Lee, Hyun Woo,Kim, Karam,Kim, Hyun,Weinberg, Richard J,Kim, Eunjoon NATURE AMERICA 2006 NATURE NEUROSCIENCE Vol.9 No.10
Synaptic cell adhesion molecules (CAMs) regulate synapse formation through their trans-synaptic and heterophilic adhesion. Here we show that postsynaptic netrin-G ligand (NGL) CAMs associate with netrin-G CAMs in an isoform-specific manner and, through their cytosolic tail, with the abundant postsynaptic scaffold postsynaptic density–95 (PSD-95). Overexpression of NGL-2 in cultured rat neurons increased the number of PSD-95–positive dendritic protrusions. NGL-2 located on heterologous cells or beads induced functional presynaptic differentiation in contacting neurites. Direct aggregation of NGL-2 on the surface membrane of dendrites induced the clustering of excitatory postsynaptic proteins. Competitive inhibition by soluble NGL-2 reduced the number of excitatory synapses. NGL-2 knockdown reduced excitatory, but not inhibitory, synapse numbers and currents. These results suggest that NGL regulates the formation of excitatory synapses.