iScience (Nov 2021)
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
- Jonathan Li,
- Ryan G. Lim,
- Julia A. Kaye,
- Victoria Dardov,
- Alyssa N. Coyne,
- Jie Wu,
- Pamela Milani,
- Andrew Cheng,
- Terri G. Thompson,
- Loren Ornelas,
- Aaron Frank,
- Miriam Adam,
- Maria G. Banuelos,
- Malcolm Casale,
- Veerle Cox,
- Renan Escalante-Chong,
- J. Gavin Daigle,
- Emilda Gomez,
- Lindsey Hayes,
- Ronald Holewenski,
- Susan Lei,
- Alex Lenail,
- Leandro Lima,
- Berhan Mandefro,
- Andrea Matlock,
- Lindsay Panther,
- Natasha Leanna Patel-Murray,
- Jacqueline Pham,
- Divya Ramamoorthy,
- Karen Sachs,
- Brandon Shelley,
- Jennifer Stocksdale,
- Hannah Trost,
- Mark Wilhelm,
- Vidya Venkatraman,
- Brook T. Wassie,
- Stacia Wyman,
- Stephanie Yang,
- Jennifer E. Van Eyk,
- Thomas E. Lloyd,
- Steven Finkbeiner,
- Ernest Fraenkel,
- Jeffrey D. Rothstein,
- Dhruv Sareen,
- Clive N. Svendsen,
- Leslie M. Thompson,
- Hemali Phatnani, PhD,
- Justin Kwan, MD,
- Dhruv Sareen, PhD,
- James R. Broach, PhD,
- Zachary Simmons, MD,
- Ximena Arcila-Londono, MD,
- Edward B. Lee, MD, PhD,
- Vivianna M. Van Deerlin, MD, PhD,
- Neil A. Shneider, MD, PhD,
- Ernest Fraenkel, PhD,
- Lyle W. Ostrow, MD, PhD,
- Frank Baas, MD, PhD,
- Noah Zaitlen, PhD,
- James D. Berry, MD, MPH,
- Andrea Malaspina, MD, PhD,
- Pietro Fratta, MD, PhD,
- Gregory A. Cox, PhD,
- Leslie M. Thompson, PhD,
- Steve Finkbeiner, MD, PhD,
- Efthimios Dardiotis, MD, PhD,
- Timothy M. Miller, MD, PhD,
- Siddharthan Chandran, PhD,
- Suvankar Pal, MD,
- Eran Hornstein, MD, PhD,
- Daniel J. MacGowan, MD,
- Terry Heiman-Patterson, MD,
- Molly G. Hammell, PhD,
- Nikolaos.A. Patsopoulos, MD, PhD,
- Oleg Butovsky, PhD,
- Joshua Dubnau, PhD,
- Avindra Nath, MD,
- Robert Bowser, PhD,
- Matt Harms, MD,
- Mary Poss, DVM, PhD,
- Jennifer Phillips-Cremins, PhD,
- John Crary, MD, PhD,
- Nazem Atassi, MD,
- Dale J. Lange, MD,
- Darius J. Adams, MD,
- Leonidas Stefanis, MD, PhD,
- Marc Gotkine, MD,
- Robert H. Baloh, MD. PhD,
- Suma Babu, MBBS, MPH,
- Towfique Raj, PhD,
- Sabrina Paganoni, MD, PhD,
- Ophir Shalem, PhD,
- Colin Smith, MD,
- Bin Zhang, PhD,
- Brent Harris, MD, PhD,
- Iris Broce, PhD,
- Vivian Drory, MD,
- John Ravits, MD,
- Corey McMillan, PhD,
- Vilas Menon, PhD,
- Lani Wu, PhD,
- Steven Altschuler, PhD
Affiliations
- Jonathan Li
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Ryan G. Lim
- UCI MIND, University of California, Irvine, CA 92697, USA
- Julia A. Kaye
- Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA
- Victoria Dardov
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Alyssa N. Coyne
- Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Jie Wu
- Department of Biological Chemistry, University of California, Irvine, CA 92697, USA
- Pamela Milani
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Andrew Cheng
- Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Terri G. Thompson
- UCI MIND, University of California, Irvine, CA 92697, USA
- Loren Ornelas
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Aaron Frank
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Miriam Adam
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Maria G. Banuelos
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Malcolm Casale
- UCI MIND, University of California, Irvine, CA 92697, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
- Veerle Cox
- Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Renan Escalante-Chong
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- J. Gavin Daigle
- Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Emilda Gomez
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Lindsey Hayes
- Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Ronald Holewenski
- Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Susan Lei
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Alex Lenail
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Leandro Lima
- Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA
- Berhan Mandefro
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Andrea Matlock
- Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Lindsay Panther
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Natasha Leanna Patel-Murray
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Jacqueline Pham
- Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Divya Ramamoorthy
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Karen Sachs
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Brandon Shelley
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Jennifer Stocksdale
- UCI MIND, University of California, Irvine, CA 92697, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
- Hannah Trost
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Mark Wilhelm
- Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Vidya Venkatraman
- Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Brook T. Wassie
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Stacia Wyman
- Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA 92697, USA
- Stephanie Yang
- Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Jennifer E. Van Eyk
- Advanced Clinical Biosystems Research Institute, The Barbra Streisand Heart Center, The Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Thomas E. Lloyd
- Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Steven Finkbeiner
- Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease, Gladstone Institutes, University of California, San Francisco, San Francisco, CA 94158, USA; Departments of Neurology and Physiology, University of California, San Francisco, San Francisco, CA 94158, USA
- Ernest Fraenkel
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Jeffrey D. Rothstein
- Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA; Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MA 212056, USA
- Dhruv Sareen
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA
- Clive N. Svendsen
- The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Corresponding author
- Leslie M. Thompson
- UCI MIND, University of California, Irvine, CA 92697, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA; Sue and Bill Gross Stem Cell Center, University of California, Irvine, CA 92697, USA; Corresponding author
- Hemali Phatnani, PhD
- Justin Kwan, MD
- Dhruv Sareen, PhD
- James R. Broach, PhD
- Zachary Simmons, MD
- Ximena Arcila-Londono, MD
- Edward B. Lee, MD, PhD
- Vivianna M. Van Deerlin, MD, PhD
- Neil A. Shneider, MD, PhD
- Ernest Fraenkel, PhD
- Lyle W. Ostrow, MD, PhD
- Frank Baas, MD, PhD
- Noah Zaitlen, PhD
- James D. Berry, MD, MPH
- Andrea Malaspina, MD, PhD
- Pietro Fratta, MD, PhD
- Gregory A. Cox, PhD
- Leslie M. Thompson, PhD
- Steve Finkbeiner, MD, PhD
- Efthimios Dardiotis, MD, PhD
- Timothy M. Miller, MD, PhD
- Siddharthan Chandran, PhD
- Suvankar Pal, MD
- Eran Hornstein, MD, PhD
- Daniel J. MacGowan, MD
- Terry Heiman-Patterson, MD
- Molly G. Hammell, PhD
- Nikolaos.A. Patsopoulos, MD, PhD
- Oleg Butovsky, PhD
- Joshua Dubnau, PhD
- Avindra Nath, MD
- Robert Bowser, PhD
- Matt Harms, MD
- Mary Poss, DVM, PhD
- Jennifer Phillips-Cremins, PhD
- John Crary, MD, PhD
- Nazem Atassi, MD
- Dale J. Lange, MD
- Darius J. Adams, MD
- Leonidas Stefanis, MD, PhD
- Marc Gotkine, MD
- Robert H. Baloh, MD. PhD
- Suma Babu, MBBS, MPH
- Towfique Raj, PhD
- Sabrina Paganoni, MD, PhD
- Ophir Shalem, PhD
- Colin Smith, MD
- Bin Zhang, PhD
- Brent Harris, MD, PhD
- Iris Broce, PhD
- Vivian Drory, MD
- John Ravits, MD
- Corey McMillan, PhD
- Vilas Menon, PhD
- Lani Wu, PhD
- Steven Altschuler, PhD
- Journal volume & issue
-
Vol. 24,
no. 11
p. 103221
Abstract
Summary: Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.
