Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons
Abstract Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within...
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BMC
2025-01-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-025-02084-w |
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| author | Calum Harvey Alicja Nowak Sai Zhang Tobias Moll Annika K Weimer Aina Mogas Barcons Cleide Dos Santos Souza Laura Ferraiuolo Kevin Kenna Noah Zaitlen Christa Caggiano Pamela J Shaw Michael P Snyder Jonathan Mill Eilis Hannon Johnathan Cooper-Knock |
| author_facet | Calum Harvey Alicja Nowak Sai Zhang Tobias Moll Annika K Weimer Aina Mogas Barcons Cleide Dos Santos Souza Laura Ferraiuolo Kevin Kenna Noah Zaitlen Christa Caggiano Pamela J Shaw Michael P Snyder Jonathan Mill Eilis Hannon Johnathan Cooper-Knock |
| author_sort | Calum Harvey |
| collection | DOAJ |
| description | Abstract Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types. |
| format | Article |
| id | doaj-art-f9c432d77fc544418d842d2a9d99426a |
| institution | Kabale University |
| issn | 1755-8794 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj-art-f9c432d77fc544418d842d2a9d99426a2025-01-19T12:42:32ZengBMCBMC Medical Genomics1755-87942025-01-0118111410.1186/s12920-025-02084-wEvaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neuronsCalum Harvey0Alicja Nowak1Sai Zhang2Tobias Moll3Annika K Weimer4Aina Mogas Barcons5Cleide Dos Santos Souza6Laura Ferraiuolo7Kevin Kenna8Noah Zaitlen9Christa Caggiano10Pamela J Shaw11Michael P Snyder12Jonathan Mill13Eilis Hannon14Johnathan Cooper-Knock15Sheffield Institute for Translational Neuroscience (SITraN), University of SheffieldSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldDepartment of Epidemiology, University of FloridaSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldCenter for Genomics and Personalized Medicine, Stanford University School of MedicineSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldDepartment of Neurology, Brain Center Rudolf Magnus, University Medical Center UtrechtDepartments of Computational Medicine and Neurology, UCLADepartments of Computational Medicine and Neurology, UCLASheffield Institute for Translational Neuroscience (SITraN), University of SheffieldCenter for Genomics and Personalized Medicine, Stanford University School of MedicineUniversity of Exeter Medical School, University of ExeterUniversity of Exeter Medical School, University of ExeterSheffield Institute for Translational Neuroscience (SITraN), University of SheffieldAbstract Amyotrophic lateral sclerosis (ALS) lacks a specific biomarker, but is defined by relatively selective toxicity to motor neurons (MN). As others have highlighted, this offers an opportunity to develop a sensitive and specific biomarker based on detection of DNA released from dying MN within accessible biofluids. Here we have performed whole genome bisulfite sequencing (WGBS) of iPSC-derived MN from neurologically normal individuals. By comparing MN methylation with an atlas of tissue methylation we have derived a MN-specific signature of hypomethylated genomic regions, which accords with genes important for MN function. Through simulation we have optimised the selection of regions for biomarker detection in plasma and CSF cell-free DNA (cfDNA). However, we show that MN-derived DNA is not detectable via WGBS in plasma cfDNA. In support of our experimental finding, we show theoretically that the relative sparsity of lower MN sets a limit on the proportion of plasma cfDNA derived from MN which is below the threshold for detection via WGBS. Our findings are important for the ongoing development of ALS biomarkers. The MN-specific hypomethylated genomic regions we have derived could be usefully combined with more sensitive detection methods and perhaps with study of CSF instead of plasma. Indeed we demonstrate that neuronal-derived DNA is detectable in CSF. Our work is relevant for all diseases featuring death of rare cell-types.https://doi.org/10.1186/s12920-025-02084-wAmyotrophic lateral sclerosis (ALS)BiomarkerCell-free DNADNA methylationWhole-genome bisulfite sequencingIPSC-derived motor neuron |
| spellingShingle | Calum Harvey Alicja Nowak Sai Zhang Tobias Moll Annika K Weimer Aina Mogas Barcons Cleide Dos Santos Souza Laura Ferraiuolo Kevin Kenna Noah Zaitlen Christa Caggiano Pamela J Shaw Michael P Snyder Jonathan Mill Eilis Hannon Johnathan Cooper-Knock Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons BMC Medical Genomics Amyotrophic lateral sclerosis (ALS) Biomarker Cell-free DNA DNA methylation Whole-genome bisulfite sequencing IPSC-derived motor neuron |
| title | Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons |
| title_full | Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons |
| title_fullStr | Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons |
| title_full_unstemmed | Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons |
| title_short | Evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated DNA signature of human motor neurons |
| title_sort | evaluation of a biomarker for amyotrophic lateral sclerosis derived from a hypomethylated dna signature of human motor neurons |
| topic | Amyotrophic lateral sclerosis (ALS) Biomarker Cell-free DNA DNA methylation Whole-genome bisulfite sequencing IPSC-derived motor neuron |
| url | https://doi.org/10.1186/s12920-025-02084-w |
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