Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics
<jats:p>We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer’s Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late on...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media SA
2023
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| Online Access: | https://hdl.handle.net/1721.1/150408 |
| _version_ | 1811087367526678528 |
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| author | Ramamurthy, Easwaran Welch, Gwyneth Cheng, Jemmie Yuan, Yixin Gunsalus, Laura Bennett, David A Tsai, Li-Huei Pfenning, Andreas R |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Ramamurthy, Easwaran Welch, Gwyneth Cheng, Jemmie Yuan, Yixin Gunsalus, Laura Bennett, David A Tsai, Li-Huei Pfenning, Andreas R |
| author_sort | Ramamurthy, Easwaran |
| collection | MIT |
| description | <jats:p>We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer’s Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) show a strong tendency to reside in microglia-specific gene regulatory elements. Despite this significant colocalization, we find that microglia harbor more acetylation changes associated with age than with amyloid-β (Aβ) load. In contrast, we detect that an oligodendrocyte-enriched glial (OEG) population contains the majority of differentially acetylated peaks associated with Aβ load. These differential peaks reside near both early onset risk genes (<jats:italic>APP, PSEN1, PSEN2</jats:italic>) and late onset AD risk loci (including <jats:italic>BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1, FERMT2</jats:italic>), Aβ processing genes (<jats:italic>BACE1</jats:italic>), as well as genes involved in myelinating and oligodendrocyte development processes. Interestingly, a number of LOAD risk loci associated with differentially acetylated risk genes contain H3K27ac peaks that are specifically enriched in OEG. These findings implicate oligodendrocyte gene regulation as a potential mechanism by which early onset and late onset risk genes mediate their effects, and highlight the deregulation of myelinating processes in AD. More broadly, our dataset serves as a resource for the study of functional effects of genetic variants and cell type specific gene regulation in AD.</jats:p> |
| first_indexed | 2024-09-23T13:44:58Z |
| format | Article |
| id | mit-1721.1/150408 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:44:58Z |
| publishDate | 2023 |
| publisher | Frontiers Media SA |
| record_format | dspace |
| spelling | mit-1721.1/1504082023-04-05T03:23:59Z Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics Ramamurthy, Easwaran Welch, Gwyneth Cheng, Jemmie Yuan, Yixin Gunsalus, Laura Bennett, David A Tsai, Li-Huei Pfenning, Andreas R Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences <jats:p>We profile genome-wide histone 3 lysine 27 acetylation (H3K27ac) of 3 major brain cell types from hippocampus and dorsolateral prefrontal cortex (dlPFC) of subjects with and without Alzheimer’s Disease (AD). We confirm that single nucleotide polymorphisms (SNPs) associated with late onset AD (LOAD) show a strong tendency to reside in microglia-specific gene regulatory elements. Despite this significant colocalization, we find that microglia harbor more acetylation changes associated with age than with amyloid-β (Aβ) load. In contrast, we detect that an oligodendrocyte-enriched glial (OEG) population contains the majority of differentially acetylated peaks associated with Aβ load. These differential peaks reside near both early onset risk genes (<jats:italic>APP, PSEN1, PSEN2</jats:italic>) and late onset AD risk loci (including <jats:italic>BIN1, PICALM, CLU, ADAM10, ADAMTS4, SORL1, FERMT2</jats:italic>), Aβ processing genes (<jats:italic>BACE1</jats:italic>), as well as genes involved in myelinating and oligodendrocyte development processes. Interestingly, a number of LOAD risk loci associated with differentially acetylated risk genes contain H3K27ac peaks that are specifically enriched in OEG. These findings implicate oligodendrocyte gene regulation as a potential mechanism by which early onset and late onset risk genes mediate their effects, and highlight the deregulation of myelinating processes in AD. More broadly, our dataset serves as a resource for the study of functional effects of genetic variants and cell type specific gene regulation in AD.</jats:p> 2023-04-04T17:48:37Z 2023-04-04T17:48:37Z 2022 2023-04-04T17:15:34Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/150408 Ramamurthy, Easwaran, Welch, Gwyneth, Cheng, Jemmie, Yuan, Yixin, Gunsalus, Laura et al. 2022. "Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics." Frontiers in Molecular Neuroscience, 15. en 10.3389/fnmol.2022.948456 Frontiers in Molecular Neuroscience Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Frontiers Media SA Frontiers |
| spellingShingle | Ramamurthy, Easwaran Welch, Gwyneth Cheng, Jemmie Yuan, Yixin Gunsalus, Laura Bennett, David A Tsai, Li-Huei Pfenning, Andreas R Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title | Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title_full | Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title_fullStr | Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title_full_unstemmed | Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title_short | Cell type-specific histone acetylation profiling of Alzheimer’s disease subjects and integration with genetics |
| title_sort | cell type specific histone acetylation profiling of alzheimer s disease subjects and integration with genetics |
| url | https://hdl.handle.net/1721.1/150408 |
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