An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients
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...
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Elsevier
2021
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oai:doaj.org-article:b0aa201abf104ba08a6430dac01837c52021-11-20T05:08:25ZAn integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients2589-004210.1016/j.isci.2021.103221https://doaj.org/article/b0aa201abf104ba08a6430dac01837c52021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221011895https://doaj.org/toc/2589-0042Summary: 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.Jonathan LiRyan G. LimJulia A. KayeVictoria DardovAlyssa N. CoyneJie WuPamela MilaniAndrew ChengTerri G. ThompsonLoren OrnelasAaron FrankMiriam AdamMaria G. BanuelosMalcolm CasaleVeerle CoxRenan Escalante-ChongJ. Gavin DaigleEmilda GomezLindsey HayesRonald HolewenskiSusan LeiAlex LenailLeandro LimaBerhan MandefroAndrea MatlockLindsay PantherNatasha Leanna Patel-MurrayJacqueline PhamDivya RamamoorthyKaren SachsBrandon ShelleyJennifer StocksdaleHannah TrostMark WilhelmVidya VenkatramanBrook T. WassieStacia WymanStephanie YangJennifer E. Van EykThomas E. LloydSteven FinkbeinerErnest FraenkelJeffrey D. RothsteinDhruv SareenClive N. SvendsenLeslie M. ThompsonHemali Phatnani, PhDJustin Kwan, MDDhruv Sareen, PhDJames R. Broach, PhDZachary Simmons, MDXimena Arcila-Londono, MDEdward B. Lee, MD, PhDVivianna M. Van Deerlin, MD, PhDNeil A. Shneider, MD, PhDErnest Fraenkel, PhDLyle W. Ostrow, MD, PhDFrank Baas, MD, PhDNoah Zaitlen, PhDJames D. Berry, MD, MPHAndrea Malaspina, MD, PhDPietro Fratta, MD, PhDGregory A. Cox, PhDLeslie M. Thompson, PhDSteve Finkbeiner, MD, PhDEfthimios Dardiotis, MD, PhDTimothy M. Miller, MD, PhDSiddharthan Chandran, PhDSuvankar Pal, MDEran Hornstein, MD, PhDDaniel J. MacGowan, MDTerry Heiman-Patterson, MDMolly G. Hammell, PhDNikolaos.A. Patsopoulos, MD, PhDOleg Butovsky, PhDJoshua Dubnau, PhDAvindra Nath, MDRobert Bowser, PhDMatt Harms, MDMary Poss, DVM, PhDJennifer Phillips-Cremins, PhDJohn Crary, MD, PhDNazem Atassi, MDDale J. Lange, MDDarius J. Adams, MDLeonidas Stefanis, MD, PhDMarc Gotkine, MDRobert H. Baloh, MD. PhDSuma Babu, MBBS, MPHTowfique Raj, PhDSabrina Paganoni, MD, PhDOphir Shalem, PhDColin Smith, MDBin Zhang, PhDBrent Harris, MD, PhDIris Broce, PhDVivian Drory, MDJohn Ravits, MDCorey McMillan, PhDVilas Menon, PhDLani Wu, PhDSteven Altschuler, PhDElsevierarticleBiological sciencesNeuroscienceSystems neuroscienceSystems biologyOmicsScienceQENiScience, Vol 24, Iss 11, Pp 103221- (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Biological sciences Neuroscience Systems neuroscience Systems biology Omics Science Q |
| spellingShingle |
Biological sciences Neuroscience Systems neuroscience Systems biology Omics Science Q 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 An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Jonathan Li |
| title |
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| title_short |
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| title_full |
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| title_fullStr |
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| title_full_unstemmed |
An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients |
| title_sort |
integrated multi-omic analysis of ipsc-derived motor neurons from c9orf72 als patients |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/b0aa201abf104ba08a6430dac01837c5 |
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