An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

Raffaella Nativio; Yemin Lan; Greg Donahue; Simone Sidoli; Amit Berson; Ananth R. Srinivasan; Oksana Shcherbakova; Alexandre Amlie-Wolf; Ji Nie; Xiaolong Cui; Chuan He; Li San Wang; Benjamin A. Garcia; John Q. Trojanowski; Nancy M. Bonini; Shelley L. Berger

doi:10.1038/s41588-020-0696-0

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

Raffaella Nativio, Yemin Lan, Greg Donahue, Simone Sidoli, Amit Berson, Ananth R. Srinivasan, Oksana Shcherbakova, Alexandre Amlie-Wolf, Ji Nie, Xiaolong Cui, Chuan He, Li San Wang, Benjamin A. Garcia, John Q. Trojanowski, Nancy M. Bonini, Shelley L. Berger

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Abstract

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin–gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

Original language	English
Pages (from-to)	1024-1035
Number of pages	12
Journal	Nature Genetics
Volume	52
Issue number	10
DOIs	https://doi.org/10.1038/s41588-020-0696-0
State	Published - Oct 1 2020

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Nativio, R., Lan, Y., Donahue, G., Sidoli, S., Berson, A., Srinivasan, A. R., Shcherbakova, O., Amlie-Wolf, A., Nie, J., Cui, X., He, C., Wang, L. S., Garcia, B. A., Trojanowski, J. Q., Bonini, N. M., & Berger, S. L. (2020). An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease. Nature Genetics, 52(10), 1024-1035. https://doi.org/10.1038/s41588-020-0696-0

@article{492df130cd4745198ad94234f80ad7aa,

title = "An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer{\textquoteright}s disease",

abstract = "Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer{\textquoteright}s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin–gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.",

author = "Raffaella Nativio and Yemin Lan and Greg Donahue and Simone Sidoli and Amit Berson and Srinivasan, {Ananth R.} and Oksana Shcherbakova and Alexandre Amlie-Wolf and Ji Nie and Xiaolong Cui and Chuan He and Wang, {Li San} and Garcia, {Benjamin A.} and Trojanowski, {John Q.} and Bonini, {Nancy M.} and Berger, {Shelley L.}",

note = "Funding Information: We thank A. Shilatifard for the histone H3.3WT and the histone mutants H3.3K27M and H3.3K9M. We thank members of the Berger laboratory for comments on the data analyses and P. Ortega for insightful scientific discussions. This work was supported by the Kleber foundation (S.L.B. and N.M.B.), a National Institutes of Health (NIH)/ National Institute on Aging grant no. P01-AG031862 (S.L.B.) and an NIH/National Institute of Neurological Disorders and Stroke grant no. R35-NS097275 (N.M.B.). C.H. is supported by grant no. R01-HG006827. C.H. is a Howard Hughes Medical Institute Investigator. L.W. is supported by grant nos. U24-AG041689 (NIAGADS) and U54-AG052427 (Global Alliance for Chronic Diseases). A.A.-W. is supported by training grant no. T32-AG00255. B.A.G. is supported by NIH grant nos. R01-NS111997 and AI118891. J.Q.T. is supported by grant no. AG10124. Funding Information: tables were downloaded from the NIAGADS at the University of Pennsylvania (U24-AG041689-01), which is funded by the National Institute on Aging. The original paper analyzed samples from the cerebellum in addition to temporal cortex, but we only used the temporal cortex data due to the cortical origin of our H4K16ac measurements and because regulatory elements are variable across brain regions110. Custom awk-based bash scripts, available by request, were used to convert eQTL data tables into BED format, using the liftOver utility from the UCSC Genome Browser111 to convert annotations from the hg18 genome build to hg19 to overlap with the H3K27ac, H3K9ac and H3K122ac peaks. Twelve AD, 10 non-AD and 18 combined condition eQTLs were unmapped by liftOver. We then used the intersect tool from the bedtools suite112 to overlap the H3K27ac, H3K9ac and H3K122ac changed peaks (P<0.05, one-way ANOVA) with the eQTL BED files. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

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doi = "10.1038/s41588-020-0696-0",

language = "English",

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Nativio, R, Lan, Y, Donahue, G, Sidoli, S, Berson, A, Srinivasan, AR, Shcherbakova, O, Amlie-Wolf, A, Nie, J, Cui, X, He, C, Wang, LS, Garcia, BA, Trojanowski, JQ, Bonini, NM & Berger, SL 2020, 'An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease', Nature Genetics, vol. 52, no. 10, pp. 1024-1035. https://doi.org/10.1038/s41588-020-0696-0

TY - JOUR

T1 - An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

AU - Nativio, Raffaella

AU - Lan, Yemin

AU - Donahue, Greg

AU - Sidoli, Simone

AU - Berson, Amit

AU - Srinivasan, Ananth R.

AU - Shcherbakova, Oksana

AU - Amlie-Wolf, Alexandre

AU - Nie, Ji

AU - Cui, Xiaolong

AU - He, Chuan

AU - Wang, Li San

AU - Garcia, Benjamin A.

AU - Trojanowski, John Q.

AU - Bonini, Nancy M.

AU - Berger, Shelley L.

N1 - Funding Information: We thank A. Shilatifard for the histone H3.3WT and the histone mutants H3.3K27M and H3.3K9M. We thank members of the Berger laboratory for comments on the data analyses and P. Ortega for insightful scientific discussions. This work was supported by the Kleber foundation (S.L.B. and N.M.B.), a National Institutes of Health (NIH)/ National Institute on Aging grant no. P01-AG031862 (S.L.B.) and an NIH/National Institute of Neurological Disorders and Stroke grant no. R35-NS097275 (N.M.B.). C.H. is supported by grant no. R01-HG006827. C.H. is a Howard Hughes Medical Institute Investigator. L.W. is supported by grant nos. U24-AG041689 (NIAGADS) and U54-AG052427 (Global Alliance for Chronic Diseases). A.A.-W. is supported by training grant no. T32-AG00255. B.A.G. is supported by NIH grant nos. R01-NS111997 and AI118891. J.Q.T. is supported by grant no. AG10124. Funding Information: tables were downloaded from the NIAGADS at the University of Pennsylvania (U24-AG041689-01), which is funded by the National Institute on Aging. The original paper analyzed samples from the cerebellum in addition to temporal cortex, but we only used the temporal cortex data due to the cortical origin of our H4K16ac measurements and because regulatory elements are variable across brain regions110. Custom awk-based bash scripts, available by request, were used to convert eQTL data tables into BED format, using the liftOver utility from the UCSC Genome Browser111 to convert annotations from the hg18 genome build to hg19 to overlap with the H3K27ac, H3K9ac and H3K122ac peaks. Twelve AD, 10 non-AD and 18 combined condition eQTLs were unmapped by liftOver. We then used the intersect tool from the bedtools suite112 to overlap the H3K27ac, H3K9ac and H3K122ac changed peaks (P<0.05, one-way ANOVA) with the eQTL BED files. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin–gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

AB - Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin–gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

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SP - 1024

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JO - Nature Genetics

JF - Nature Genetics

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ER -

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

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