. 2024 May 24;384(6698):eadh0559.

doi: 10.1126/science.adh0559. Epub 2024 May 24.

Massively parallel characterization of regulatory elements in the developing human cortex

Chengyu Deng^#^{1

2}, Sean Whalen^#³, Marilyn Steyert^{4

5

6

7

8

9}, Ryan Ziffra^{1

4

5}, Pawel F Przytycki³, Fumitaka Inoue¹⁰, Daniela A Pereira^{1

2

11}, Davide Capauto¹², Scott Norton¹², Flora M Vaccarino^{12

13}; PsychENCODE Consortium‡; Alex A Pollen^{8

9

14

15}, Tomasz J Nowakowski^{4

5

6

8

9

15}, Nadav Ahituv^{1

2}, Katherine S Pollard^{2

3

7

16}; PsychENCODE Consortium

Collaborators, Affiliations

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul A Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-Fan Chien, Zhiyuan Chu, Declan Clarke, Ashley Clement, Leonardo Collado-Torres, Gregory M Cooper, Gregory E Crawford, Rujia Dai, Nikolaos P Daskalakis, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc Duong, Cagatay Dursun, Nicholas J Eagles, Jonathan Edelstein, Prashant S Emani, John F Fullard, Kiki Galani, Timur Galeev, Michael J Gandal, Sophia Gaynor, Mark Gerstein, Daniel H Geschwind, Kiran Girdhar, Fernando S Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Gabriel E Hoffman, Yiling Huang, Louise A Huuki-Myers, Ahyeon Hwang, Thomas M Hyde, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Saniya Khullar, Joel E Kleinman, Steven P Kleopoulos, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Chunyu Liu, Shuang Liu, Shaoke Lou, Jacob M Loupe, Dan Lu, Shaojie Ma, Liang Ma, Michael Margolis, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Samantha Mazariegos, Ran Meng, Richard M Myers, Courtney Micallef, Tatiana Mikhailova, Guo-Li Ming, Shahin Mohammadi, Emma Monte, Kelsey S Montgomery, Jill E Moore, Jennifer R Moran, Eran A Mukamel, Angus C Nairn, Charles B Nemeroff, Pengyu Ni, Scott Norton, Tomasz Nowakowski, Larsson Omberg, Stephanie C Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Mette A Peters, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Katherine S Pollard, Alex Pollen, Henry Pratt, Pawel F Przytycki, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Diana Quintero, Towfique Raj, Ananya S Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Panos Roussos, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nenad Sestan, Nicholas Seyfried, Zhiping Shao, Nicole Shedd, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Jason Stein, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael Snyder, Ran Tao, Karen Therrien, Li-Huei Tsai, Alexander E Urban, Flora M Vaccarino, Harm van Bakel, Daniel Vo, Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Yu Wei, Annika K Weimer, Daniel R Weinberger, Cindy Wen, Zhiping Weng, Sean Whalen, Kevin P White, A Jeremy Willsey, Hyejung Won, Wing Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X Yap, Biao Zeng, Pan Zhang, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane R Zeier, Trisha M Zintel

Affiliations

¹ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
² Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Gladstone Institutes, San Francisco, CA 94158, USA.
⁴ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Chan Zuckerberg Biohub, San Francisco, San Francisco, CA 94158, USA.
⁸ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143, USA.
⁹ Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA.
¹⁰ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan.
¹¹ Graduate Program of Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
¹² Child Study Center, Yale University, New Haven, CT 06520, USA.
¹³ Department of Neuroscience, Yale University, New Haven, CT 06520, USA.
¹⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁵ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.

^# Contributed equally.

PMID: 38781390
DOI: 10.1126/science.adh0559

Massively parallel characterization of regulatory elements in the developing human cortex

Chengyu Deng et al. Science. 2024.

. 2024 May 24;384(6698):eadh0559.

doi: 10.1126/science.adh0559. Epub 2024 May 24.

Authors

Collaborators

Schahram Akbarian, Alexej Abyzov, Nadav Ahituv, Dhivya Arasappan, Jose Juan Almagro Armenteros, Brian J Beliveau, Jaroslav Bendl, Sabina Berretta, Rahul A Bharadwaj, Arjun Bhattacharya, Lucy Bicks, Kristen Brennand, Davide Capauto, Frances A Champagne, Tanima Chatterjee, Chris Chatzinakos, Yuhang Chen, H Isaac Chen, Yuyan Cheng, Lijun Cheng, Andrew Chess, Jo-Fan Chien, Zhiyuan Chu, Declan Clarke, Ashley Clement, Leonardo Collado-Torres, Gregory M Cooper, Gregory E Crawford, Rujia Dai, Nikolaos P Daskalakis, Jose Davila-Velderrain, Amy Deep-Soboslay, Chengyu Deng, Christopher P DiPietro, Stella Dracheva, Shiron Drusinsky, Ziheng Duan, Duc Duong, Cagatay Dursun, Nicholas J Eagles, Jonathan Edelstein, Prashant S Emani, John F Fullard, Kiki Galani, Timur Galeev, Michael J Gandal, Sophia Gaynor, Mark Gerstein, Daniel H Geschwind, Kiran Girdhar, Fernando S Goes, William Greenleaf, Jennifer Grundman, Hanmin Guo, Qiuyu Guo, Chirag Gupta, Yoav Hadas, Joachim Hallmayer, Xikun Han, Vahram Haroutunian, Natalie Hawken, Chuan He, Ella Henry, Stephanie C Hicks, Marcus Ho, Li-Lun Ho, Gabriel E Hoffman, Yiling Huang, Louise A Huuki-Myers, Ahyeon Hwang, Thomas M Hyde, Artemis Iatrou, Fumitaka Inoue, Aarti Jajoo, Matthew Jensen, Lihua Jiang, Peng Jin, Ting Jin, Connor Jops, Alexandre Jourdon, Riki Kawaguchi, Manolis Kellis, Saniya Khullar, Joel E Kleinman, Steven P Kleopoulos, Alex Kozlenkov, Arnold Kriegstein, Anshul Kundaje, Soumya Kundu, Cheyu Lee, Donghoon Lee, Junhao Li, Mingfeng Li, Xiao Lin, Shuang Liu, Jason Liu, Jianyin Liu, Chunyu Liu, Shuang Liu, Shaoke Lou, Jacob M Loupe, Dan Lu, Shaojie Ma, Liang Ma, Michael Margolis, Jessica Mariani, Keri Martinowich, Kristen R Maynard, Samantha Mazariegos, Ran Meng, Richard M Myers, Courtney Micallef, Tatiana Mikhailova, Guo-Li Ming, Shahin Mohammadi, Emma Monte, Kelsey S Montgomery, Jill E Moore, Jennifer R Moran, Eran A Mukamel, Angus C Nairn, Charles B Nemeroff, Pengyu Ni, Scott Norton, Tomasz Nowakowski, Larsson Omberg, Stephanie C Page, Saejeong Park, Ashok Patowary, Reenal Pattni, Geo Pertea, Mette A Peters, Nishigandha Phalke, Dalila Pinto, Milos Pjanic, Sirisha Pochareddy, Katherine S Pollard, Alex Pollen, Henry Pratt, Pawel F Przytycki, Carolin Purmann, Zhaohui S Qin, Ping-Ping Qu, Diana Quintero, Towfique Raj, Ananya S Rajagopalan, Sarah Reach, Thomas Reimonn, Kerry J Ressler, Deanna Ross, Panos Roussos, Joel Rozowsky, Misir Ruth, W Brad Ruzicka, Stephan J Sanders, Juliane M Schneider, Soraya Scuderi, Robert Sebra, Nenad Sestan, Nicholas Seyfried, Zhiping Shao, Nicole Shedd, Annie W Shieh, Joo Heon Shin, Mario Skarica, Clara Snijders, Hongjun Song, Matthew W State, Jason Stein, Marilyn Steyert, Sivan Subburaju, Thomas Sudhof, Michael Snyder, Ran Tao, Karen Therrien, Li-Huei Tsai, Alexander E Urban, Flora M Vaccarino, Harm van Bakel, Daniel Vo, Georgios Voloudakis, Brie Wamsley, Tao Wang, Sidney H Wang, Daifeng Wang, Yifan Wang, Jonathan Warrell, Yu Wei, Annika K Weimer, Daniel R Weinberger, Cindy Wen, Zhiping Weng, Sean Whalen, Kevin P White, A Jeremy Willsey, Hyejung Won, Wing Wong, Hao Wu, Feinan Wu, Stefan Wuchty, Dennis Wylie, Siwei Xu, Chloe X Yap, Biao Zeng, Pan Zhang, Chunling Zhang, Bin Zhang, Jing Zhang, Yanqiong Zhang, Xiao Zhou, Ryan Ziffra, Zane R Zeier, Trisha M Zintel

Affiliations

¹ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
² Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Gladstone Institutes, San Francisco, CA 94158, USA.
⁴ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Chan Zuckerberg Biohub, San Francisco, San Francisco, CA 94158, USA.
⁸ Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA 94143, USA.
⁹ Weill Institute for Neurosciences, University of California, San Francisco, CA 94158, USA.
¹⁰ Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan.
¹¹ Graduate Program of Genetics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
¹² Child Study Center, Yale University, New Haven, CT 06520, USA.
¹³ Department of Neuroscience, Yale University, New Haven, CT 06520, USA.
¹⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁵ Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁶ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94158, USA.

^# Contributed equally.

PMID: 38781390
DOI: 10.1126/science.adh0559

Abstract

Nucleotide changes in gene regulatory elements are important determinants of neuronal development and diseases. Using massively parallel reporter assays in primary human cells from mid-gestation cortex and cerebral organoids, we interrogated the cis-regulatory activity of 102,767 open chromatin regions, including thousands of sequences with cell type-specific accessibility and variants associated with brain gene regulation. In primary cells, we identified 46,802 active enhancer sequences and 164 variants that alter enhancer activity. Activity was comparable in organoids and primary cells, suggesting that organoids provide an adequate model for the developing cortex. Using deep learning we decoded the sequence basis and upstream regulators of enhancer activity. This work establishes a comprehensive catalog of functional gene regulatory elements and variants in human neuronal development.

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Massively parallel characterization of psychiatric disorder-associated and cell-type-specific regulatory elements in the developing human cortex.
Deng C, Whalen S, Steyert M, Ziffra R, Przytycki PF, Inoue F, Pereira DA, Capauto D, Norton S, Vaccarino FM, Pollen A, Nowakowski TJ, Ahituv N, Pollard KS. Deng C, et al. bioRxiv [Preprint]. 2023 Feb 16:2023.02.15.528663. doi: 10.1101/2023.02.15.528663. bioRxiv. 2023. Update in: Science. 2024 May 24;384(6698):eadh0559. doi: 10.1126/science.adh0559. PMID: 36824845 Free PMC article. Updated. Preprint.

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Massively parallel characterization of regulatory elements in the developing human cortex

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Massively parallel characterization of regulatory elements in the developing human cortex

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