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2. The three-dimensional landscape of cortical chromatin accessibility in Alzheimer’s disease

Author

Bendl, Jaroslav, Hauberg, Mads E., Girdhar, Kiran, Im, Eunju, Vicari, James M., Rahman, Samir, Fernando, Michael B., Townsley, Kayla G., Dong, Pengfei, Misir, Ruth, Kleopoulos, Steven P., Reach, Sarah M., Apontes, Pasha, Zeng, Biao, Zhang, Wen, Voloudakis, Georgios, Brennand, Kristen J., Nixon, Ralph A., Haroutunian, Vahram, Hoffman, Gabriel E., Fullard, John F., and Roussos, Panos

Published
2022
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4. Neuronal impact of patient-specific aberrant NRXN1α splicing

Author

Flaherty, Erin, Zhu, Shijia, Barretto, Natalie, Cheng, Esther, Deans, P. J. Michael, Fernando, Michael B., Schrode, Nadine, Francoeur, Nancy, Antoine, Alesia, Alganem, Khaled, Halpern, Madeline, Deikus, Gintaras, Shah, Hardik, Fitzgerald, Megan, Ladran, Ian, Gochman, Peter, Rapoport, Judith, Tsankova, Nadejda M., McCullumsmith, Robert, Hoffman, Gabriel E., Sebra, Robert, Fang, Gang, and Brennand, Kristen J.

Published
2019
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6. List of contributors

Author

Abdolmaleky, Hamid Mostafavi, primary, Akbarian, Schahram, additional, Ambrosini, Alexander, additional, Avramopoulos, Dimitrios, additional, Bendersky, Cari J., additional, Bendl, Jaroslav, additional, Bérubé, Nathalie G., additional, Bhat, Unis Ahmad, additional, Borreggine, Kristin, additional, Braun, Patricia R., additional, Brennand, Kristen J., additional, Castro, Amanda, additional, Chakravarty, Sumana, additional, Chang, Connie, additional, Cohen, Sophie, additional, Coppedè, Fabio, additional, Dahrendorff, Jan, additional, Dunn, Jeffrey T., additional, Eberwine, James H., additional, Elia, Josephine, additional, Fang, Gang, additional, Fels, Samuel, additional, Fernando, Michael B., additional, Franklin, Tamara Brook, additional, Fries, Gabriel R., additional, Frizzola, Meg, additional, Fullard, John F., additional, Ganguly, Sebanti, additional, Gapp, Katharina, additional, Garcia, Meilin Fernandez, additional, Gatta, Eleonora, additional, Grayson, Dennis R., additional, Gropman, Andrea L., additional, Guidotti, Alessandro, additional, Gupta, Praveer, additional, Hakonarson, Hakon, additional, Hunter, Richard G., additional, Imamura, Takuya, additional, Izaki, Yumiko, additional, Jakub, Taryn, additional, Keung, Crystal, additional, Kramer, Jamie M., additional, Kumar, Arvind, additional, Kundakovic, Marija, additional, Labonté, Benoit, additional, LaMarca, Elizabeth A., additional, Lee, Richard S., additional, Lima, Camila N.C., additional, Lutz, Pierre-Eric, additional, Matt, Stephanie M., additional, Milian, Allison A., additional, Miyashiro, Kevin Y., additional, Murgatroyd, Chris, additional, Nakashima, Kinichi, additional, Paul, Bidisha, additional, Peedicayil, Jacob, additional, Pinjari, Omar F., additional, Poddar, Karuna, additional, Potash, James B., additional, Powell, Samuel K., additional, Quesnel, Katerine, additional, Rayfield, Jessica, additional, Reddy, R. Gajendra, additional, Richter, Troy A., additional, Roth, Eric D., additional, Roth, Tania L., additional, Roussos, Panos, additional, Ruzicka, W. Brad, additional, Salarda, Erika M., additional, Santhosh, Samuel, additional, Saudagar, Vikram, additional, Stoccoro, Andrea, additional, Syed, Shariful A., additional, Thiagalingam, Sam, additional, Tollefsbol, Trygve O., additional, Turecki, Gustavo, additional, Uddin, Monica, additional, Uesaka, Masahiro, additional, Walker, Deena, additional, Yamamoto, Naoki, additional, Yost, Oliver, additional, and Zannas, Anthony S., additional

Published
2021
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7. Lineage specific 3D genome structure in the adult human brain and neurodevelopmental changes in the chromatin interactome

Author

Rahman, Samir, primary, Dong, Pengfei, additional, Apontes, Pasha, additional, Fernando, Michael B, additional, Kosoy, Roman, additional, Townsley, Kayla G, additional, Girdhar, Kiran, additional, Bendl, Jaroslav, additional, Shao, Zhiping, additional, Misir, Ruth, additional, Tsankova, Nadia, additional, Kleopoulos, Steven P, additional, Brennand, Kristen J, additional, Fullard, John F, additional, and Roussos, Panos, additional

Published
2023
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8. R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription

Author

LaMarca, Elizabeth A., primary, Saito, Atsushi, additional, Plaza-Jennings, Amara, additional, Hellmich, Allyse, additional, Fernando, Michael B., additional, Javidfar, Behnam, additional, Espeso-Gil, Sergio, additional, Estill, Molly, additional, Liao, Will, additional, Townsley, Kayla, additional, Florio, Anna, additional, Ethridge, James E., additional, Do, Catherine, additional, Tycko, Benjamin, additional, Shen, Li, additional, Kamiya, Atsushi, additional, Tsankova, Nadejda M., additional, Brennand, Kristen J., additional, and Akbarian, Schahram, additional

Published
2023
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9. Upregulated GIRK2 counteracts ethanol-induced changes in excitability and respiration in human neurons

Author

Prytkova, Iya A., primary, Liu, Yiyuan, additional, Fernando, Michael B., additional, Gameiro-Ros, Isabel, additional, Popova, Dina, additional, Kamarajan, Chella, additional, Xuei, Xiaoling, additional, Chorlian, David B., additional, Edenberg, Howard J., additional, Tischfield, Jay A., additional, Porjesz, Bernice, additional, Pang, Zhiping P., additional, Hart, Ronald P., additional, Goate, Alison M., additional, and Slesinger, Paul A., additional

Published
2023
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11. From compartments to gene loops: Functions of the 3D genome in the human brain

Author

Rahman, Samir, primary, Dong, Pengfei, additional, Apontes, Pasha, additional, Fernando, Michael B., additional, Townsley, Kayla G., additional, Girdhar, Kiran, additional, Bendl, Jaroslav, additional, Shao, Zhiping, additional, Misir, Ruth, additional, Tsankova, Nadia, additional, Kleopoulos, Steven P., additional, Brennand, Kristen J., additional, Fullard, John F., additional, and Roussos, Panos, additional

Published
2021
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14. Common Genetic Variation in Humans Impacts In Vitro Susceptibility to SARS-CoV-2 Infection

Author

Dobrindt, Kristina, primary, Hoagland, Daisy A., additional, Seah, Carina, additional, Kassim, Bibi, additional, O'Shea, Callan P., additional, Murphy, Aleta, additional, Iskhakova, Marina, additional, Fernando, Michael B., additional, Powell, Samuel K., additional, Deans, P.J. Michael, additional, Javidfar, Ben, additional, Peter, Cyril, additional, Møller, Rasmus, additional, Uhl, Skyler A., additional, Garcia, Meilin Fernandez, additional, Kimura, Masaki, additional, Iwasawa, Kentaro, additional, Crary, John F., additional, Kotton, Darrell N., additional, Takebe, Takanori, additional, Huckins, Laura M., additional, tenOever, Benjamin R., additional, Akbarian, Schahram, additional, and Brennand, Kristen J., additional

Published
2021
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16. Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer’s Disease

Author

Wang, Minghui, primary, Li, Aiqun, additional, Sekiya, Michiko, additional, Beckmann, Noam D., additional, Quan, Xiuming, additional, Schrode, Nadine, additional, Fernando, Michael B., additional, Yu, Alex, additional, Zhu, Li, additional, Cao, Jiqing, additional, Lyu, Liwei, additional, Horgusluoglu, Emrin, additional, Wang, Qian, additional, Guo, Lei, additional, Wang, Yuan-shuo, additional, Neff, Ryan, additional, Song, Won-min, additional, Wang, Erming, additional, Shen, Qi, additional, Zhou, Xianxiao, additional, Ming, Chen, additional, Ho, Seok-Man, additional, Vatansever, Sezen, additional, Kaniskan, H. Ümit, additional, Jin, Jian, additional, Zhou, Ming-Ming, additional, Ando, Kanae, additional, Ho, Lap, additional, Slesinger, Paul A., additional, Yue, Zhenyu, additional, Zhu, Jun, additional, Katsel, Pavel, additional, Gandy, Sam, additional, Ehrlich, Michelle E., additional, Fossati, Valentina, additional, Noggle, Scott, additional, Cai, Dongming, additional, Haroutunian, Vahram, additional, Iijima, Koichi M., additional, Schadt, Eric, additional, Brennand, Kristen J., additional, and Zhang, Bin, additional

Published
2021
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17. Common genetic variation in humans impactsin vitrosusceptibility to SARS-CoV-2 infection

Author

Dobrindt, Kristina, primary, Hoagland, Daisy A., additional, Seah, Carina, additional, Kassim, Bibi, additional, O’Shea, Callan P., additional, Iskhakova, Marina, additional, Fernando, Michael B., additional, Deans, P.J. Michael, additional, Powell, Samuel K., additional, Javidfar, Ben, additional, Murphy, Aleta, additional, Peter, Cyril, additional, Møeller, Rasmus, additional, Garcia, Meilin Fernandez, additional, Kimura, Masaki, additional, Iwasawa, Kentaro, additional, Crary, John, additional, Kotton, Darrell N., additional, Takebe, Takanori, additional, Huckins, Laura M., additional, tenOever, Benjamin R., additional, Akbarian, Schahram, additional, and Brennand, Kristen J., additional

Published
2020
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18. ASCL1- and DLX2-induced GABAergic neurons from hiPSC-derived NPCs

Author

Barretto, Natalie, primary, Zhang, Hanwen, additional, Powell, Samuel K., additional, Fernando, Michael B., additional, Zhang, Siwei, additional, Flaherty, Erin K., additional, Ho, Seok-Man, additional, Slesinger, Paul A., additional, Duan, Jubao, additional, and Brennand, Kristen J., additional

Published
2020
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20. Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Author

Wang, Minghui, primary, Li, Aiqun, additional, Sekiya, Michiko, additional, Beckmann, Noam D., additional, Quan, Xiuming, additional, Schrode, Nadine, additional, Fernando, Michael B., additional, Yu, Alex, additional, Zhu, Li, additional, Cao, Jiqing, additional, Lyu, Liwei, additional, Horgusluoglu, Emrin, additional, Wang, Qian, additional, Guo, Lei, additional, Wang, Yuan-shuo, additional, Neff, Ryan, additional, Song, Won-min, additional, Wang, Erming, additional, Shen, Qi, additional, Zhou, Xianxiao, additional, Ming, Chen, additional, Ho, Seok-Man, additional, Vatansever, Sezen, additional, Kaniskan, H. Umit, additional, Jin, Jian, additional, Zhou, Ming-Ming, additional, Ando, Kanae, additional, Ho, Lap, additional, Slesinger, Paul A., additional, Yue, Zhenyu, additional, Zhu, Jun, additional, Gandy, Sam, additional, Ehrlich, Michelle E., additional, Cai, Dongming, additional, Haroutunian, Vahram, additional, Iijima, Koichi M., additional, Schadt, Eric, additional, Brennand, Kristen J., additional, and Zhang, Bin, additional

Published
2019
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22. Phenotypic complexities of rare heterozygous neurexin-1 deletions.

Author

Fernando MB, Fan Y, Zhang Y, Tokolyi A, Murphy AN, Kammourh S, Michael Deans PJ, Ghorbani S, Onatzevitch R, Pero A, Padilla C, Williams S, Flaherty EK, Prytkova IA, Cao L, Knowles DA, Fang G, Slesinger PA, and Brennand KJ

Abstract

Given the large number of genes significantly associated with risk for neuropsychiatric disorders, a critical unanswered question is the extent to which diverse mutations --sometimes impacting the same gene-- will require tailored therapeutic strategies. Here we consider this in the context of rare neuropsychiatric disorder-associated copy number variants (2p16.3) resulting in heterozygous deletions in NRXN1 , a pre-synaptic cell adhesion protein that serves as a critical synaptic organizer in the brain. Complex patterns of NRXN1 alternative splicing are fundamental to establishing diverse neurocircuitry, vary between the cell types of the brain, and are differentially impacted by unique (non-recurrent) deletions. We contrast the cell-type-specific impact of patient-specific mutations in NRXN1 using human induced pluripotent stem cells, finding that perturbations in NRXN1 splicing result in divergent cell-type-specific synaptic outcomes. Via distinct loss-of-function (LOF) and gain-of-function (GOF) mechanisms, NRXN1 +/- deletions cause decreased synaptic activity in glutamatergic neurons, yet increased synaptic activity in GABAergic neurons. Reciprocal isogenic manipulations causally demonstrate that aberrant splicing drives these changes in synaptic activity. For NRXN1 deletions, and perhaps more broadly, precision medicine will require stratifying patients based on whether their gene mutations act through LOF or GOF mechanisms, in order to achieve individualized restoration of NRXN1 isoform repertoires by increasing wildtype, or ablating mutant isoforms. Given the increasing number of mutations predicted to engender both LOF and GOF mechanisms in brain disorders, our findings add nuance to future considerations of precision medicine., Competing Interests: Ethics declarations / Competing interest statement. All authors have no competing interests to declare.

Published
2024
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23. R-loop landscapes in the developing human brain are linked to neural differentiation and cell-type specific transcription.

Author

LaMarca EA, Saito A, Plaza-Jennings A, Espeso-Gil S, Hellmich A, Fernando MB, Javidfar B, Liao W, Estill M, Townsley K, Florio A, Ethridge JE, Do C, Tycko B, Shen L, Kamiya A, Tsankova NM, Brennand KJ, and Akbarian S

Abstract

Here, we construct genome-scale maps for R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in the proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix, with preferential formation at promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations and defective functional and structural neuronal connectivity in vivo and in vitro . Therefore, R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells., Competing Interests: DECLARATION OF INTERESTS The authors declare no conflicts of interest.

Published
2023
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24. Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection.

Author

Dobrindt K, Hoagland DA, Seah C, Kassim B, O'Shea CP, Iskhakova M, Fernando MB, Deans PJM, Powell SK, Javidfar B, Murphy A, Peter C, Møeller R, Garcia MF, Kimura M, Iwasawa K, Crary J, Kotton DN, Takebe T, Huckins LM, tenOever BR, Akbarian S, and Brennand KJ

Abstract

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying comorbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3'UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro . Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease., Competing Interests: CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.

Published
2020
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