Reduced Expression of the Epigenetic Regulator CBX5 Leads to Widespread Transcriptional Dysregulation in Multiple Sclerosis Patients

Core Concepts

Reduced activity of the epigenetic regulator CBX5 in a subset of multiple sclerosis patients leads to impaired maturation of non-coding RNAs and altered RNA polymerase II pause-release, resulting in extensive transcriptional deregulation of genes relevant to the disease.

Abstract

The study examined the transcriptome of monocytes from multiple sclerosis (MS) patients and identified a subset with reduced expression of the epigenetic regulator CBX5. These patients exhibited extensive transcriptional deregulation, including:

Impaired maturation of U snRNAs and enhancer RNAs (eRNAs), indicative of reduced activity of the Integrator complex.
Altered RNA polymerase II (RNAPII) pause-release, leading to increased transcription at the 5' regions of genes but decreased production of full-length mRNAs.
Aberrant splicing, with increased exon skipping at genes associated with MS.
Upregulation of genes involved in inflammation and amino acid transport, as well as ectopic expression of genes like leptin.

The authors propose that reduced CBX5 activity, potentially through its regulation of the Integrator complex, is a major contributor to the transcriptional anomalies characteristic of MS. This is supported by a mouse model with Cbx5 inactivation, which recapitulated many of the transcriptional defects observed in the low-CBX5 MS patients and exhibited exacerbated symptoms in an experimental autoimmune encephalomyelitis (EAE) model.

Stats

"Patients with low CBX5 expression displayed 1395 upregulated and 1350 downregulated genes (2-fold or more, adj. pVal<0.05, baseMean>10) compared to symptomatic controls."
"In the Cbx5-/- mouse model, a total of 6478 genes were differentially regulated (3224 up and 3248 down, 2-fold or more, Adj pVal<0.05)."
"Among the 3224 upregulated genes in the Cbx5-/- mice, 703 were also upregulated by EAE, corresponding to approximately half of the genes upregulated by EAE."

Quotes

"Reduced Integrator activity translates into either up- or down-regulation of numerous genes associated with multiple sclerosis (MS), the outcome possibly varying depending on the extent to which these genes rely on RNAPII pause-release for their regulation."
"The reduced expression of AHI1, which is strongly linked to a higher risk of MS, might be due either to SNPs as previously reported, or to decreased Integrator activity."
"The seemingly abortive ferroptosis in the MS patients may further suggest that this defense mechanism is not entirely functional in these patients, possibly participating in the exacerbated neuroinflammation."

Key Insights Distilled From

Defective Integrator activity shapes the transcriptome of patients with multiple sclerosis

by Porozhan,Y.,... at www.biorxiv.org 11-24-2023

https://www.biorxiv.org/content/10.1101/2023.11.24.568591v2

Deeper Inquiries

What other epigenetic or transcriptional regulators might be involved in the pathogenesis of multiple sclerosis, and how could they interact with the Integrator complex?

Multiple sclerosis (MS) is a complex disease with a multifactorial etiology involving genetic, environmental, and epigenetic factors. Apart from the Integrator complex, several other epigenetic and transcriptional regulators may play a role in the pathogenesis of MS. One key player is the Polycomb Repressive Complex 2 (PRC2), which is involved in histone methylation and gene silencing. Dysregulation of PRC2 has been implicated in autoimmune diseases, including MS. PRC2 may interact with the Integrator complex by modulating chromatin structure and gene expression, thereby influencing the transcriptional landscape in MS patients.
Another important regulator is DNA methylation, which is controlled by DNA methyltransferases (DNMTs). Aberrant DNA methylation patterns have been observed in MS patients, affecting gene expression and contributing to disease pathogenesis. DNMTs may interact with the Integrator complex to regulate gene expression by modulating the accessibility of DNA to transcription factors and RNA polymerase.
Furthermore, histone acetyltransferases (HATs) and histone deacetylases (HDACs) are critical regulators of histone acetylation, a key epigenetic modification that influences gene expression. Dysregulation of HATs and HDACs has been linked to autoimmune diseases, including MS. These enzymes may interact with the Integrator complex to modulate chromatin structure and transcriptional activity, thereby impacting the pathogenesis of MS.
Overall, the Integrator complex likely interacts with a network of epigenetic and transcriptional regulators, including PRC2, DNMTs, HATs, and HDACs, to orchestrate gene expression patterns in MS patients. Understanding the crosstalk between these regulators is essential for unraveling the complex transcriptional dysregulation observed in MS.

How might the observed transcriptional anomalies, such as ectopic gene expression and altered splicing, contribute to the development and progression of multiple sclerosis symptoms?

The observed transcriptional anomalies, including ectopic gene expression and altered splicing, can have profound implications for the development and progression of multiple sclerosis (MS) symptoms. Ectopic gene expression, characterized by the aberrant activation of genes in non-canonical locations, can lead to the production of proteins with diverse functions that may contribute to neuroinflammation, demyelination, and neuronal damage in MS. For example, the activation of retroviral elements due to defective enhancer RNA (eRNA) processing can trigger an immune response and promote inflammation in the central nervous system.
Altered splicing, such as exon skipping and intron retention, can disrupt the normal production of functional proteins and regulatory RNAs, leading to cellular dysfunction and dysregulation of key pathways involved in MS pathogenesis. For instance, the dysregulation of splicing events at genes encoding autoantigens or immune modulators can impact immune responses and contribute to the autoimmune process in MS.
Moreover, the dysregulated transcriptional activity associated with the Integrator complex dysfunction can affect the expression of genes involved in ferroptosis, a form of regulated cell death characterized by lipid peroxidation. Enhanced ferroptosis due to transcriptional anomalies may exacerbate neuroinflammation and neuronal damage in MS, further worsening disease progression.
Overall, the transcriptional anomalies observed in MS patients, including ectopic gene expression and altered splicing, can disrupt normal cellular functions, dysregulate immune responses, and promote neuroinflammation, ultimately contributing to the development and progression of MS symptoms.

Could the insights from this study be leveraged to develop novel therapeutic strategies that target the underlying transcriptional dysregulation in multiple sclerosis?

The insights gained from this study on the role of the Integrator complex in transcriptional dysregulation in multiple sclerosis (MS) offer promising avenues for the development of novel therapeutic strategies that target the underlying molecular mechanisms of the disease. Here are some potential therapeutic approaches based on the findings:

Targeting the Integrator complex: Modulating the activity of the Integrator complex, either through small molecule inhibitors or activators, could help restore normal transcriptional regulation in MS patients. By enhancing the function of the Integrator complex, it may be possible to correct the aberrant splicing and gene expression patterns observed in MS.

Epigenetic modifiers: Targeting epigenetic regulators that interact with the Integrator complex, such as histone modifiers or DNA methyltransferases, could offer a way to modulate gene expression and chromatin structure in MS. By restoring proper epigenetic marks, it may be possible to normalize transcriptional activity and mitigate disease progression.

RNA-based therapies: Utilizing RNA-targeting approaches, such as antisense oligonucleotides or RNA interference, to specifically modulate the expression of genes affected by transcriptional anomalies in MS could be a promising therapeutic strategy. By targeting specific transcripts or splicing events, it may be possible to correct the dysregulated gene expression patterns.

Immunomodulatory agents: Given the role of transcriptional dysregulation in immune responses in MS, immunomodulatory agents that target specific pathways affected by the Integrator complex dysfunction could help regulate the inflammatory processes underlying the disease. Targeting key immune genes with altered expression profiles could help restore immune homeostasis.

In conclusion, the insights from this study provide a foundation for the development of precision therapies that target the transcriptional dysregulation in MS, offering new opportunities for personalized treatment strategies that address the molecular mechanisms driving the disease.