Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease

Li, Hong Dong; Funk, Cory C.; McFarland, Karen N.; Dammer, Eric B.; Allen, Mariet; Carrasquillo, Minerva M.; Levites, Yona; Chakrabarty, Paramita; Burgess, Jeremy D.; Wang, Xue; Dickson, Dennis W.; Seyfried, Nicholas T.; Duong, Duc M.; Lah, James J.; Younkin, Steven G.; Levey, Aĺlan I.; Omenn, Gilbert S.; Ertekin-Taner, Nilüfer; Golde, Todd E.; Price, Nathan D.

doi:10.1002/alz.12254

Cited by 29 publications

(34 citation statements)

References 73 publications

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“…Importantly, we find reproducible alterations of specific RNA editing events in the context of AD. This is similar to our recent report of reproducible splicing alterations in AD 10 and the broader narrative of specific disruptions in RNA maturation 10 , 11 and in the epigenome in relation to AD 12 . Our list of top genes associated with AD does not overlap with that from the genetic studies of AD, and none of the RNA editing events located in the AD relevant genes reported by the genetic studies reached a genome-wide significance threshold (Table S6 ), suggesting that changes in RNA editing in AD are unlikely to be related to genetic risk factors or to affect the same targets.…”

Section: Discussionsupporting

confidence: 92%

Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Dammer

Felsky

et al. 2021

Nat Commun

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RNA editing is a feature of RNA maturation resulting in the formation of transcripts whose sequence differs from the genome template. Brain RNA editing may be altered in Alzheimer’s disease (AD). Here, we analyzed data from 1,865 brain samples covering 9 brain regions from 1,074 unrelated subjects on a transcriptome-wide scale to identify inter-regional differences in RNA editing. We expand the list of known brain editing events by identifying 58,761 previously unreported events. We note that only a small proportion of these editing events are found at the protein level in our proteome-wide validation effort. We also identified the occurrence of editing events associated with AD dementia, neuropathological measures and longitudinal cognitive decline in: SYT11, MCUR1, SOD2, ORAI2, HSDL2, PFKP, and GPRC5B. Thus, we present an extended reference set of brain RNA editing events, identify a subset that are found to be expressed at the protein level, and extend the narrative of transcriptomic perturbation in AD to RNA editing.

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Section: Discussionsupporting

confidence: 92%

Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Dammer

Felsky

et al. 2021

Nat Commun

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“…UPF2, as noted above, plays an important role in mRNA surveillance and the degradation of transcripts by NMD that contain premature stop codons through mutations or missplicing events. We have previously shown that aggregation of RNA binding proteins that are involved in mRNA splicing is an early event in AD pathogenesis, and likely leads to aberrant mRNA splicing events that may give rise to premature stop codons or alternative exon-exon junctions 10,38,39,[65][66][67] . These proteins, such as U1 small nuclear ribonucleoprotein 70 kDa (SNRNP70, or U1-70K) and others that are part of the U1 spliceosome complex, have been shown to interact with NFTs through their low-complexity basic-acidic domains, and were strongly enriched in the M13 RNA splicing module 68 .…”

Section: Discussionmentioning

confidence: 99%

Large-Scale Deep Multi-Layer Analysis of Alzheimer’s Disease Brain Reveals Strong Proteomic Disease-Related Changes Not Observed at the RNA Level

Johnson

Dammer

et al. 2021

Preprint

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The biological processes that are disrupted in the Alzheimer's disease (AD) brain remain incompletely understood. We recently performed a proteomic analysis of >2000 brains to better understand these changes, which highlighted alterations in astrocytes and microglia as likely key drivers of disease. Here, we extend this analysis by analyzing >1000 brain tissues using a tandem mass tag mass spectrometry (TMT-MS) pipeline, which allowed us to nearly triple the number of quantified proteins across cases. A consensus protein co-expression network analysis of this deeper dataset revealed new co-expression modules that were highly preserved across cohorts and brain regions, and strongly altered in AD. Nearly half of the protein co-expression modules, including modules significantly altered in AD, were not observed in RNA networks from the same cohorts and brain regions, highlighting the proteopathic nature of AD. Two such AD-associated modules unique to the proteomic network included a module related to MAPK signaling and metabolism, and a module related to the matrisome. Analysis of paired genomic and proteomic data within subjects showed that expression level of the matrisome module was influenced by the APOE ε4 genotype, but was not related to the rate of cognitive decline after adjustment for neuropathology. In contrast, the MAPK/metabolism module was strongly associated with the rate of cognitive decline. Disease-associated modules unique to the proteome are sources of promising therapeutic targets and biomarkers for AD.

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“…However, DS genes in AD exhibited few overlaps with those previously identi ed in brain transcriptome data (Supplementary Fig. 4B-C) [31,32], highlighting the tissue-speci city of splicing events.…”

Section: Stat1 a Key Transcription Regulator Of Type I Ifn Signaling Is Differentially Spliced In Scdmentioning

confidence: 54%

Impaired type I interferon signaling activity implicated in the peripheral blood transcriptome of preclinical Alzheimer’s disease

Song

Chen

et al. 2021

Preprint

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Subjective cognitive decline (SCD) is considered the preclinical manifestation of Alzheimer’s disease (AD), which is a potentially crucial window for preventing or delaying the progression of the disease. To explore the potential mechanism of disease progression and identify relevant biomarkers, we comprehensively assessed the peripheral blood transcriptomic alterations in SCD, covering lncRNA, mRNA, and miRNA. Dysregulated protein-coding mRNA at both gene and isoform levels implicated impairment in the type I interferon signaling pathway in SCD. Specifically, this pathway was regulated by the transcription factor STAT1 and ncRNAs NRIR and has-miR-146a-5. The miRNA-mRNA-lncRNA coexpression network revealed hub genes for the interferon module. Individuals with lower interferon signaling activity and lower expression of hub genes STAT1 and TRIM22 exhibited a higher conversion rate to mild cognitive impairment (MCI). Our findings illustrated the down-regulation of interferon signaling activity would potentially increase the risk of disease progression and thus serve as a pre-disease biomarker.

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Integrative functional genomic analysis of intron retention in human and mouse brain with Alzheimer's disease

Cited by 29 publications

References 73 publications

Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue

Large-Scale Deep Multi-Layer Analysis of Alzheimer’s Disease Brain Reveals Strong Proteomic Disease-Related Changes Not Observed at the RNA Level

Impaired type I interferon signaling activity implicated in the peripheral blood transcriptome of preclinical Alzheimer’s disease

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