Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease

Nativio, Raffaella; Donahue, Greg; Berson, Amit; Lan, Yemin; Amlie‐Wolf, Alexandre; Tüzer, Ferit; Toledo, Jon B.; Gosai, Sager J.; Gregory, Brian D.; Torres, Claudio; Trojanowski, John Q.; Wang, Li-San; Johnson, F. Brad; Bonini, Nancy M.; Berger, Shelley L.

doi:10.1038/s41593-018-0101-9

Cited by 255 publications

(284 citation statements)

References 69 publications

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“…To test the relevance of this phenomenon for lncRNAs at large and for LINC‐PINT specifically, we measured the expression of LINC‐PINT in AD and HD by investigating brain expression data from WADs of effected individuals and neurologically normal controls. We identified a 45% elevation of LINC‐PINT in the lateral temporal lobe of AD patients compared to healthy donors (Figure h, GSE104704) (Nativio et al, ). LINC‐PINT elevation in AD was also reproduced in our own RNA‐Seq cohort (Barbash, Garfinkel, et al, ), where patients were divided into sub‐groups based on their cognitive impairment and their brain pathology.…”

Section: Resultsmentioning

confidence: 89%

A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

et al. 2020

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Recent reports highlight regulatory functions of long noncoding RNAs (lncRNAs) in neurodegeneration and aging, but biomedical implications remain limited. Here, we report an rRNA‐depletion‐based long RNA‐Sequencing Resource of 65 substantia nigra, amygdala, and medial temporal gyrus samples from Parkinson's disease (PD) and matched control brains. Using a lncRNA‐focused analysis approach to identify functionally important transcripts, we discovered and prioritized many lncRNAs dysregulated in PD. Those included pronounced elevation of the P53‐induced noncoding transcript LINC‐PINT in the substantia nigra of PD patients, as well as in additional models of oxidative stress and PD. Intriguingly, we found that LINC‐PINT is a primarily neuronal transcript which showed conspicuous increases in maturing primary culture neurons. LINC‐PINT also accumulated in several brain regions of Alzheimer's and Huntington's disease patients and decreased with healthy brain aging, suggesting a general role in aging and neurodegeneration for this lncRNA. RNAi‐mediated depletion of LINC‐PINT exacerbated the death of cultured N2A and SH‐SY5Y cells exposed to oxidative stress, highlighting a previously undiscovered neuroprotective role for this tumor‐inducible lncRNA in the brains of patients with neurodegenerative disorders.

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Section: Resultsmentioning

confidence: 89%

A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

et al. 2020

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“…Differential peaking analysis has suggested that there is more peak loss in AD patients [24]. H4K16ac, another aging-related active transcription marks also indicated a tendency of H4K16ac mark loss [23]. Tau protein burden is reported to have a broad effect on the epigenome [19].…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide studies of CpG islands identified altered DNA methylation and suggested their impacts on the AD risk genes [22]. Histone modification studies to active epigenetic marks, such as H4K16ac, H3K9acand H3K27ac, suggested that abnormal epigenetic regulation affects the regulation of AD genes [23,24]. Additionally, recent studies reported that large-scale changes in H3K27ac could be driven by tau pathology in human brains [19] and that HDAC3 inhibition could reverse AD-related pathologies in the animal model of AD [25].…”

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confidence: 99%

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Meng

Yuan

et al. 2019

Preprint

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Alzheimer's disease (AD) is extremely complex for both causal mechanism and clinical manifestation, requiring efforts to uncover its diversity and the corresponding mechanisms. Here, we applied a modelling analysis to investigate the regulation divergence among a large-scale cohort of AD patients. We found that transcription regulation tended to get degenerated in AD patients, which contributed to disease development and the detrimental clinical outcomes, mainly by disrupting protein degradation, neuroinflammation, mitochondrial and synaptic functions. To measure the accumulated effects, we came up with a new concept, regulation loss burden, which better correlated with AD related clinical manifestations and the ageing process. The epigenetic studies to multiple active regulation marks also supported a tendency of regulation loss in AD patients. Our finding can lead to a unified model as AD causal mechanism, where AD and its diversity are contributed by accumulated degeneration of transcriptional regulation.The significance of this study is that: (1) it is the first system biology investigation to transcription regulation divergence among AD patients; (2) we observed an accumulated degeneration of transcription regulation, which well correlates with detrimental clinical outcomes; (3) transcriptional degeneration also contributes to the ageing process, where its correlation with ages is up to 0.78. IntroductionAlzheimer's disease (AD) is a complex chronic neurodegenerative disease that has been intensively studied for decades. However, its causal mechanismd remain elusive [1]. More attentions have been focused on the visible neuropathological features, especially the amyloid plaques and neurofibrillary tangles. Amyloid plaques are composed of depositions of insoluble and densely packed amyloid beta (A ) protein whereas neurofibrillary tangles are composed of aggregations of hyperphosphorylated tau protein [2]. Early-onset AD studies in rare families led to the discovery of three genes, amyloid precursor protein, presenilin 1, and presenilin 2 that demonstrated the causal effects of A in the AD progression [3]. However, this is challenged 1 by the observation that some patients with substantial accumulations of plaques have no cognitive impairment [4] and that drugs targeting A all failed in clinical studies [5]. Although neurofibrillary tangles have a stronger correlation with the decline of cognitive ability and have drawn more attentions recently [6,7], strong or direct evidence linking neurofibrillary tangles to AD is still lacking [8].Integrated systematic approaches, especially coexpression regulatory network analysis, have advanced our understanding of AD in different ways [9,10,11]. In such studies, biological networks are constructed using gene-expression data to identify the gene modules related to AD genesis and development by integrating quantitative evaluation into both AD neuropathology and cognitive ability decline. In our previous work, we studied transcriptional dysregulation between AD patients an...

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“…Furthermore, recent studies in AD have relied on bulk tissue (16)(17)(18), potentially masking epigenomic changes that occur in rare cell types. For example, microglia constitute around 5% of brain cells, therefore analysis of bulk tissue renders microglia-specific enhancers difficult to detect.…”

Section: Introductionmentioning

confidence: 99%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

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Identification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants. AbstractUnique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring ADrisk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function. of neurons, microglia, astrocytes, oligodendrocytes and other cell types that reside within the brain (1-4). In contrast, transcriptional mechanisms that control their developmental and functional properties in health and disease remain less well understood. Studies in animal models have provided deep insights into conserved processes, but significant differences between species often limit the translatability of findings in model systems to humans (5).Genome-wide association studies (GWASs) provide a genetic approach to identifying molecular pathways involved in complex traits and diseases by defining associations between genetic variants and phenotypes of interest (6, 7). Large-scale GWASs have discovered hundreds of single nucleotide polymorphisms (SNPs) that are associated with the risk of neurological and psychiatric disorders. The vast majority of disease-risk genetic variants are located in non-coding regions of the genome (7) and the specific cell type (s) in which the disease-risk variants are active is often unclear. Furthermore, linkagedisequilibrium between disease-risk variants at GWAS significant loci complicates the identification of causal variants. Collectively, these limitations have hindered the assignment and interpretation of disease-risk genes.GWAS-identified risk variants that are located in non-coding regions of the genome can exert phenotypic effects through several mechanisms, including perturbation of transcriptional enhancers and promoters (6). While promoters provide the essential sites of transcriptional initiation of mRNAs, they are frequently not sufficient to direct appropriate developmental and signal-dependent levels of gene expression (8,9). This additional information is provided by enhancers, short regions of DNA that, when bound by transcription factors, enhance mRNA expression from target promoters. Enhancers can reside hundreds of thousands of base pairs away from their target gene and their function is generally consid...

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Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease

Cited by 255 publications

References 69 publications

A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

A lncRNA survey finds increases in neuroprotective LINC‐PINT in Parkinson’s disease substantia nigra

Accumulated degeneration of transcriptional regulation contributes to disease development and detrimental clinical outcomes of Alzheimer’s disease

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

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