Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease.
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| Title: | Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease. |
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| Authors: | Zhang, Yang (AUTHOR), Lu, Xinyue (AUTHOR), Kunisky, Alexander K. (AUTHOR), Alam, Shahul (AUTHOR), Tang, Junjie (AUTHOR), Zhang, Ruochi (AUTHOR), Wang, Shike (AUTHOR), Zhang, Han (AUTHOR), Baroudi, Jude (AUTHOR), Ichcho, Walid (AUTHOR), Jia, Deyong (AUTHOR), Ghorbanikalateh, Sahar (AUTHOR), Ghorbanikalateh, Sahel (AUTHOR), Wang, Shihan (AUTHOR), Bennett, David A. (AUTHOR), Mathys, Hansruedi (AUTHOR), Duan, Zhijun (AUTHOR), Ma, Jian (AUTHOR) |
| Source: | Science. 7/23/2026, Vol. 393 Issue 6809, p1-14. 14p. |
| Abstract: | Alzheimer's disease (AD) disrupts brain function through cell type–specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type–specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type–specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration. INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia and is marked by progressive loss of brain function. Many studies have cataloged changes in gene activity across brain cell types; however, the molecular mechanisms underlying these changes remain elusive. Gene activity is controlled not only by DNA sequence and chemical marks on DNA but also by how the genome is folded in three dimensions inside the nucleus. How this three-dimensional (3D) genome organization changes in AD and how such changes relate to cell type–specific gene dysregulation in the human brain remain poorly understood. RATIONALE: We aimed to determine whether changes in 3D genome folding are linked to the gene expression programs disrupted in AD and whether these links can be detected at single-cell resolution in human brain tissue. To do this, we used GAGE-seq (genome architecture and gene expression by sequencing), a technology that measures, in the same single cell, both gene expression and physical contacts within the genome. We integrated these measurements with chromatin accessibility data from the same donors and with spatial transcriptome maps in intact tissue sections, enabling analyses across molecular, cellular, and tissue scales. We also developed a transformer-based predictive model that integrates DNA sequence with 3D genome features to test when genome structure is necessary to explain AD-related gene expression changes. RESULTS: Across major brain cell types, we observed a reproducible shift in genome contact patterns in AD, including reduced short-range interactions and increased longer-range interactions. Although overall compartment patterns were broadly preserved, active and inactive genome regions showed increased mixing, consistent with weakened compartment segregation. These architectural changes were linked to broad, cell type–specific transcriptional remodeling of disease-relevant pathways, and we further related these programs to the current landscape of AD clinical trial targets. At regulatory elements identified by chromatin accessibility, promoter-proximal interactions weakened, while midrange regulatory interactions became relatively more prominent, particularly at sites associated with chromatin loop organization. In parallel, we observed AD-related changes in key cellular programs, including senescence-related activation in microglia and sex-dependent dysregulation of X-linked genes in females, accompanied by corresponding 3D genome changes at implicated loci. Our predictive model showed that 3D genome features provide information beyond DNA sequence alone for explaining AD-relevant gene expression, enabling prioritization of distal regulatory elements whose effects are mediated through chromatin contacts. Integrating these molecular features with spatial transcriptomics further placed them in tissue context, revealing altered cell neighborhoods and disrupted spatial coordination of gene programs in AD. Overall, the study connects genome structure, gene regulation, and tissue organization through a unified multimodal analysis. CONCLUSION: These results provide a multiscale map linking 3D genome remodeling to cell type–specific gene expression changes and spatial tissue organization in AD. The study establishes genome folding as a key regulatory layer associated with AD pathology and provides a framework and resource for mechanistic hypothesis generation, including prioritization of regulatory elements and AD-relevant gene programs for future functional testing and therapeutic exploration. 3D genome remodeling in Alzheimer's disease.: Single-cell multimodal GAGE-seq maps 3D genome organization and transcriptome in AD. The disease-relevant genome structural shifts track altered gene regulation. Integration with spatial transcriptomics uncovers altered spatial cellular niches reflecting in situ dynamics of the 3D genome in AD. Coupling GAGE-seq with Hicformer, a transformer-based model, further reveals an essential regulatory role of the 3D genome in AD. snATAC-seq, single-nucleus assay for transposase-accessible chromatin using sequencing. [ABSTRACT FROM AUTHOR] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 195791515 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Zhang%2C+Yang%22">Zhang, Yang</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lu%2C+Xinyue%22">Lu, Xinyue</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kunisky%2C+Alexander+K%2E%22">Kunisky, Alexander K.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Alam%2C+Shahul%22">Alam, Shahul</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Tang%2C+Junjie%22">Tang, Junjie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Ruochi%22">Zhang, Ruochi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Shike%22">Wang, Shike</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Zhang%2C+Han%22">Zhang, Han</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Baroudi%2C+Jude%22">Baroudi, Jude</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ichcho%2C+Walid%22">Ichcho, Walid</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Jia%2C+Deyong%22">Jia, Deyong</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ghorbanikalateh%2C+Sahar%22">Ghorbanikalateh, Sahar</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ghorbanikalateh%2C+Sahel%22">Ghorbanikalateh, Sahel</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wang%2C+Shihan%22">Wang, Shihan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bennett%2C+David+A%2E%22">Bennett, David A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Mathys%2C+Hansruedi%22">Mathys, Hansruedi</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Duan%2C+Zhijun%22">Duan, Zhijun</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ma%2C+Jian%22">Ma, Jian</searchLink> (AUTHOR) – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 7/23/2026, Vol. 393 Issue 6809, p1-14. 14p. – Name: Abstract Label: Abstract Group: Ab Data: Alzheimer's disease (AD) disrupts brain function through cell type–specific transcriptomic and epigenomic alterations, yet the contribution of three-dimensional (3D) genome organization to AD remains poorly understood. We applied GAGE-seq (genome architecture and gene expression by sequencing) to jointly profile gene expression and 3D chromatin structure in single cells from postmortem brain tissue from AD patients and age-matched individuals without AD, revealing chromatin reorganization linked to cell type–specific dysregulation. Integrations with spatial transcriptomics and chromatin accessibility data uncovered altered niches reflecting genome compartment remodeling and regulatory element reorganization. Hicformer, a deep learning framework, showed that 3D genome features are essential for predicting disease-relevant, cell type–specific gene expression changes. Our results establish higher-order chromatin alterations as a component of AD-associated molecular pathology, providing a multiscale view of transcriptional regulation and 3D genome organization in neurodegeneration. INTRODUCTION: Alzheimer's disease (AD) is the most common cause of dementia and is marked by progressive loss of brain function. Many studies have cataloged changes in gene activity across brain cell types; however, the molecular mechanisms underlying these changes remain elusive. Gene activity is controlled not only by DNA sequence and chemical marks on DNA but also by how the genome is folded in three dimensions inside the nucleus. How this three-dimensional (3D) genome organization changes in AD and how such changes relate to cell type–specific gene dysregulation in the human brain remain poorly understood. RATIONALE: We aimed to determine whether changes in 3D genome folding are linked to the gene expression programs disrupted in AD and whether these links can be detected at single-cell resolution in human brain tissue. To do this, we used GAGE-seq (genome architecture and gene expression by sequencing), a technology that measures, in the same single cell, both gene expression and physical contacts within the genome. We integrated these measurements with chromatin accessibility data from the same donors and with spatial transcriptome maps in intact tissue sections, enabling analyses across molecular, cellular, and tissue scales. We also developed a transformer-based predictive model that integrates DNA sequence with 3D genome features to test when genome structure is necessary to explain AD-related gene expression changes. RESULTS: Across major brain cell types, we observed a reproducible shift in genome contact patterns in AD, including reduced short-range interactions and increased longer-range interactions. Although overall compartment patterns were broadly preserved, active and inactive genome regions showed increased mixing, consistent with weakened compartment segregation. These architectural changes were linked to broad, cell type–specific transcriptional remodeling of disease-relevant pathways, and we further related these programs to the current landscape of AD clinical trial targets. At regulatory elements identified by chromatin accessibility, promoter-proximal interactions weakened, while midrange regulatory interactions became relatively more prominent, particularly at sites associated with chromatin loop organization. In parallel, we observed AD-related changes in key cellular programs, including senescence-related activation in microglia and sex-dependent dysregulation of X-linked genes in females, accompanied by corresponding 3D genome changes at implicated loci. Our predictive model showed that 3D genome features provide information beyond DNA sequence alone for explaining AD-relevant gene expression, enabling prioritization of distal regulatory elements whose effects are mediated through chromatin contacts. Integrating these molecular features with spatial transcriptomics further placed them in tissue context, revealing altered cell neighborhoods and disrupted spatial coordination of gene programs in AD. Overall, the study connects genome structure, gene regulation, and tissue organization through a unified multimodal analysis. CONCLUSION: These results provide a multiscale map linking 3D genome remodeling to cell type–specific gene expression changes and spatial tissue organization in AD. The study establishes genome folding as a key regulatory layer associated with AD pathology and provides a framework and resource for mechanistic hypothesis generation, including prioritization of regulatory elements and AD-relevant gene programs for future functional testing and therapeutic exploration. 3D genome remodeling in Alzheimer's disease.: Single-cell multimodal GAGE-seq maps 3D genome organization and transcriptome in AD. The disease-relevant genome structural shifts track altered gene regulation. Integration with spatial transcriptomics uncovers altered spatial cellular niches reflecting in situ dynamics of the 3D genome in AD. Coupling GAGE-seq with Hicformer, a transformer-based model, further reveals an essential regulatory role of the 3D genome in AD. snATAC-seq, single-nucleus assay for transposase-accessible chromatin using sequencing. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.adz1652 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 14 StartPage: 1 Titles: – TitleFull: Single-cell multiomics connects 3D genome and transcriptome alterations in Alzheimer's disease. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Zhang, Yang – PersonEntity: Name: NameFull: Lu, Xinyue – PersonEntity: Name: NameFull: Kunisky, Alexander K. – PersonEntity: Name: NameFull: Alam, Shahul – PersonEntity: Name: NameFull: Tang, Junjie – PersonEntity: Name: NameFull: Zhang, Ruochi – PersonEntity: Name: NameFull: Wang, Shike – PersonEntity: Name: NameFull: Zhang, Han – PersonEntity: Name: NameFull: Baroudi, Jude – PersonEntity: Name: NameFull: Ichcho, Walid – PersonEntity: Name: NameFull: Jia, Deyong – PersonEntity: Name: NameFull: Ghorbanikalateh, Sahar – PersonEntity: Name: NameFull: Ghorbanikalateh, Sahel – PersonEntity: Name: NameFull: Wang, Shihan – PersonEntity: Name: NameFull: Bennett, David A. – PersonEntity: Name: NameFull: Mathys, Hansruedi – PersonEntity: Name: NameFull: Duan, Zhijun – PersonEntity: Name: NameFull: Ma, Jian IsPartOfRelationships: – BibEntity: Dates: – D: 23 M: 07 Text: 7/23/2026 Type: published Y: 2026 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 393 – Type: issue Value: 6809 Titles: – TitleFull: Science Type: main |
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