Harvard Study Finds That Cognition-Associated Long Noncoding RNAs Are Dysregulated Upon Severe COVID-19
Nikhil Prasad Fact checked by:Thailand Medical News Team Feb 13, 2024 10 months, 1 week, 2 days, 2 hours, 59 minutes ago
COVID-19 News: The global COVID-19 pandemic has brought forth numerous challenges, extending beyond the acute respiratory symptoms commonly associated with the virus. Increasing evidence suggests a link between severe COVID-19 and cognitive decline, prompting researchers to explore the molecular underpinnings of this phenomenon. In a groundbreaking study conducted by Harvard Medical School and Brigham and Women's Hospital in Boston, USA, and covered in this
COVID-19 News report, researchers delved into the intricate world of long noncoding RNAs (lncRNAs) to unravel the transcriptomic changes associated with severe COVID-19 and their potential implications on cognitive function.
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Severe COVID-19 changes the expression of long non-coding RNAs (lncRNAs) in the human frontal cortex. (A) Age and sex of individuals with COVID-19 and uninfected age/sex-matched control ( ± 2 years) groups (n=22/group) analyzed in this cohort; for further details see Mavrikaki et al. (5). (B) Tabulation of differentially expressed RNA species identified in our sequencing study. (C) Volcano plot showing the differentially expressed non-coding genes in the frontal cortex of COVID-19 cases versus age/sex-matched controls (n=22/group). Red points, significantly upregulated genes among COVID-19 cases (false discovery rate/FDR < 0.05). Blue points, significantly downregulated genes among COVID-19 cases. Black points, highlighted significant genes with corresponding gene symbols. (D) T-distributed stochastic neighbor embedding (TSNE) analysis of frontal cortex of COVID-19 cases and uninfected age/sex-matched controls, using significant differentially expressed noncoding RNA (ncRNA) expression levels as features. Black border, 23-year-old asymptomatic COVID-19 male. Red border, 62-year-old COVID-19 female individual with comorbid epilepsy. Blue border, 84-year-old COVID-19 female individual with comorbid Alzheimer’s Disease (AD). Green border, uninfected age/sex-matched control for the COVID case with comorbid AD. n=22/group. (E) Guilt-by-association-based Gene Ontology (GO) biological pathway analysis of top differentially expressed ncRNAs and NEAT1, a lncRNA involved in cognitive processes (18). (F) Validation of sequencing data using qRT-PCR. n=22/group. Two tailed unpaired t-test, *p<0.05, **p<0.01, ***p<0.001. LINC01007 t(42)= 5.377, p=0.000003, LINC00294 t(42)= 2.224, p=0.0316, LINC01094 t(42)= 2.844, p=0.0069, NEAT1 t(42)= 2.583, p=0.0134.
Understanding Long Noncoding RNAs:
Long noncoding RNAs, a class of RNA molecules with limited protein-coding potential, have emerged as key players in the regulation of gene expression. Ranging from 200 base pairs to hundreds of kilobases, lncRNAs act as crucial regulators, influencing transcriptional states through various mechanisms. Acting as scaffolds to recruit transcription factors and effectors to their target genes, lncRNAs can exert their influence in both cis and trans, regulating genes near their locus or across
the genome. These molecules have been linked to synaptic plasticity, memory, and various brain disorders, making them a compelling focus for understanding the cognitive impact of severe COVID-19.
The Study's Approach and Findings
The research team analyzed total RNA-seq datasets obtained from the frontal cortex of individuals with severe COVID-19 and age/sex-matched uninfected controls. The results revealed significant dysregulation of both coding and noncoding RNAs, with 557 upregulated and 269 downregulated noncoding RNAs, including various lncRNAs. Clustering analysis demonstrated a distinct separation between COVID-19 cases and controls, emphasizing the pervasive transcriptomic changes induced by the virus.
Key lncRNAs Implicated
Among the identified lncRNAs, LINC01007 and LINC01094 stood out as top differentially expressed molecules. Strikingly, these lncRNAs exhibited similar expression patterns to those observed in the brains of aged individuals and Alzheimer's Disease (AD) patients. Additional lncRNAs linked to brain aging and AD, such as NEAT1, LINC00643, LINC00507, and MALAT1, were also implicated, underscoring the potential significance of these lncRNAs in COVID-19-related cognitive changes.
Pathway Analysis and Validation
To gain insights into the functional roles of the identified lncRNAs, the researchers performed guilt-by-association pathway analysis. This analysis implicated several lncRNAs in pathways associated with cognitive functions such as memory and learning. Furthermore, the differential expression of key lncRNAs, including LINC01007, LINC01094, and NEAT1, was validated using quantitative real-time polymerase chain reaction (qRT-PCR). The association of NEAT1 with cognitive decline was reinforced by previous studies demonstrating its negative impact on cognitive function when overexpressed.
Correlation with Cognitive Performance
To assess the relevance of these findings to cognitive performance, the researchers utilized cognitive and transcriptomic data from the ROSMAP cohort. Strikingly, the dysregulated lncRNAs associated with severe COVID-19 were also linked to poor cognitive performance, as evidenced by Gene Set Enrichment Analysis (GSEA). This association persisted even when considering COVID-19 cases with a history of intensive care unit or ventilator treatment, emphasizing the potential role of lncRNAs independent of these treatments.
Link to Neuroinflammation
As inflammation has been implicated in COVID-19-related neurological effects, the study explored the expression changes of lncRNAs in primary human neurons upon cytokine treatment. Nineteen lncRNAs were identified as differentially expressed both in severe COVID-19 and poor cognition. Notably, LINC01094, NEAT1, and LINC00643, previously linked to brain aging and AD, were among the overlapping genes. Additionally, the study uncovered the potential regulatory role of antisense lncRNAs on corresponding protein-coding genes involved in inflammation.
Discussion and Future Implications
The study sheds light on the intricate relationship between severe COVID-19, cognitive decline, and dysregulated lncRNAs. While the focus was on severe cases due to specimen availability, the findings prompt speculation about potential lncRNA expression changes in milder cases. The identified lncRNAs present as promising therapeutic targets to modulate neuroinflammation and alleviate cognitive deficits associated with COVID-19. This comprehensive exploration of lncRNA dynamics provides a foundation for future research aimed at understanding the molecular mechanisms underlying COVID-19-related neurological consequences and developing targeted interventions to mitigate cognitive impairment.
The study findings were published in the peer reviewed journal: Frontiers in Immunology.
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1290523/full
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