The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

Desi, Ng; Tay, Yvonne

doi:10.3390/cells8121634

Cited by 9 publications

(5 citation statements)

References 196 publications

(190 reference statements)

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“…Others have similarly shown that cells display a sensitive dependence to initial conditions (in this case, gene expression), and that very small changes in transcriptional regulation and equilibrium may exert potent perhaps even chaotic impacts on disease progression (90,91).…”

Section: Discussionmentioning

confidence: 99%

The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

Clemens

Sivakumar

Pius

et al. 2021

eLife

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Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

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Section: Discussionmentioning

confidence: 99%

The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

Clemens

Sivakumar

Pius

et al. 2021

eLife

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“…Hence, we may under- or overestimate biological effects based on our interpretation of the differential gene expression results 24 h after injection. Also, posttranscriptional ( 87 ) and posttranslational mechanisms ( 88 ) may account, among other things, for a non-linear correlation between mRNA and protein abundance. These shortcomings may also contribute to an explanation as to why the CLH, which features many of the same differentially regulated gene transcripts as the ILH, does not feature morphological alterations.…”

Section: Discussionmentioning

confidence: 99%

Differential Glial Activation in Early Epileptogenesis—Insights From Cell-Specific Analysis of DNA Methylation and Gene Expression in the Contralateral Hippocampus

et al. 2020

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Background and Aims: Morphological changes in mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) are well-characterized. Yet, it remains elusive whether these are a consequence of seizures or originate from a hitherto unknown underlying pathology. We recently published data on changes in gene expression and DNA methylation in the ipsilateral hippocampus (ILH) using the intracortical kainate mouse model of mTLE-HS. In order to explore the effects of epileptic activity alone and also to further disentangle what triggers morphological alterations, we investigated glial and neuronal changes in gene expression and DNA methylation in the contralateral hippocampus (CLH). Methods: The intracortical kainic acid mouse model of mTLE-HS was used to elicit status epilepticus. Hippocampi contralateral to the injection site from eight kainate-injected and eight sham mice were extracted and shock frozen at 24 h post-injection. Glial and neuronal nuclei were sorted by flow cytometry. Alterations in gene expression and DNA methylation were assessed using reduced representation bisulfite sequencing and RNA sequencing. The R package edgeR was used for statistical analysis. Results: The CLH featured substantial, mostly cell-specific changes in both gene expression and DNA methylation in glia and neurons. While changes in gene expression overlapped to a great degree between CLH and ILH, alterations in DNA methylation did not. In the CLH, we found a significantly lower number of glial genes up- and downregulated compared to previous results from the ILH. Furthermore, several genes and pathways potentially involved in anti-epileptogenic effects were upregulated in the CLH. By comparing gene expression data from the CLH to previous results from the ILH (featuring hippocampal sclerosis), we derive potential upstream targets for epileptogenesis, including glial Cox2 and Cxcl10 . Conclusion: Despite the absence of morphological changes, the CLH displays substantial changes in gene expression and DNA methylation. We find that gene expression changes related to potential anti-epileptogenic effects seem to dominate compared to the pro-epileptogenic effects in the CLH and speculate whether this imbalance contributes to prevent morphological alterations like neuronal death and reactive gliosis.

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“…What is being detected in this study are the further downstream (larger) effects of a biological pathway initiated at the base change. Reminiscent of a "butterfly effect", where a single base change can lead to a cascade of changes, leading to increasingly larger effect sizes down the biological pathway that can be more readily detected [16,17]. Receiver Operating Characteristic (ROC) curves for PRS were generated for the BDR cohort using the IGAP (A) and Jansen (B) summary statistics.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Classification Accuracy of Expression Quantitative Trait Loci Calculated Polygenic Risk Scores in Alzheimer’s Disease

Brookes

2023

IJMS

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Polygenic risk scores (PRS) hold promise for the early identification of those at risk from neurodegenerative disorders such as Alzheimer’s Disease (AD), allowing for intervention to occur prior to neuronal damage. The current selection of informative single nucleotide polymorphisms (SNPs) to generate the risk scores is based on the modelling of large genome-wide association data using significance thresholds. However, the biological relevance of these SNPs is largely unknown. This study, in contrast, aims to identify SNPs with biological relevance to AD and then assess them for their ability to accurately classify cases and controls. Samples selected from the Brains for Dementia Research (BDR) were used to produce gene expression data to identify potential expression quantitative trait loci (eQTLs) relevant to AD. These SNPs were then incorporated into a PRS model to classify AD and controls in the full BDR cohort. Models derived from these eQTLs demonstrate modest classification potential with an accuracy between 61% and 67%. Although the model accuracy is not as high as some values in the literature based on significance thresholds from genome-wide association studies, these models may reflect a more biologically relevant model, which may provide novel targets for therapeutic intervention.

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The Butterfly Effect of RNA Alterations on Transcriptomic Equilibrium

Cited by 9 publications

References 196 publications

The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

Differential Glial Activation in Early Epileptogenesis—Insights From Cell-Specific Analysis of DNA Methylation and Gene Expression in the Contralateral Hippocampus

Evaluating the Classification Accuracy of Expression Quantitative Trait Loci Calculated Polygenic Risk Scores in Alzheimer’s Disease

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