Abnormal RNA Transcription in Human Disease: Molecular Mechanisms and Clinical Implications

A Comprehensive Analysis of Transcriptional Dysregulation

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Figure 1: Mechanisms of Transcription Dysregulation

1. Cancer: Oncogenic Transcription Addiction

A. Transcription Factor Dysregulation

• MYC Overactivation:

  • Gene amplification → 10-40× overexpression

  • Binds 15% of promoters → ribosomal biogenesis hyperactivation

• p53 Inactivation:

  • Mutant p53 fails to repress MDM2 → uncontrolled cell cycling

  • Present in >50% of solid tumors

B. RNA Polymerase Machinery Defects

Therapeutic Target:

• α-Amanitin antibody-drug conjugates selectively degrade mutant RNAP II

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2. Neurodegenerative Disorders

A. Repeat Expansion Disorders

• C9orf72 ALS/FTD:

  • GGGGCC repeats → RAN translation of toxic dipeptides

  • Sequesters RNAP II in nuclear foci

• Huntington’s Disease:

  • CAG repeats in HTT → RNAP II stalling

  • Global transcription suppression

B. RNAP II Pausing Defects

Mechanism of Alzheimer’s progression via transcription impairment

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3. Developmental Disorders

A. Cohesinopathies (e.g., Cornelia de Lange)

• Mutant Proteins: NIPBL, SMC1A, SMC3

• Transcription Impact:

  • Disrupted enhancer-promoter looping

  • 60% reduction in RAD21-dependent genes

B. Congenital Heart Defects

• TBX5 Haploinsufficiency:

  • Reduced binding to cardiac enhancers

  • Impaired MYH6, *NKX2-5* expression

• Clinical Correlation:

  • 78% of Holt-Oram syndrome cases show TBX5-dependent transcription defects

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4. Autoimmune Diseases

A. SLE (Systemic Lupus Erythematosus)

• RNAP III Dysregulation:

  • Anti-RNAP III antibodies → Altered tRNA/5S rRNA synthesis

• Consequence:

  • Nucleolar stress → interferon signature

B. Rheumatoid Arthritis

• BET Protein Overactivation:

  • BRD4 hyperphosphorylation → super-enhancer formation

  • TNF-α, IL-6 overexpression

Treatment: JQ1 (BET inhibitor) reduces inflammation

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5. Therapeutic Approaches

A. Transcription-Targeted Therapies

B. Clinical Trial Outcomes

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6. Diagnostic Biomarkers

Liquid Biopsy Applications

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7. Future Research Frontiers

A. Single-Cell Transcriptomics

• Spatio-Temporal Mapping:

  • Resolve transcription bursting in tumor subclones

• Clinical Impact:

  • Identify pre-malignant transcription states

B. RNAP II Chaperone Therapies

• HSF1 Activators:

  • Recover transcription in proteinopathies

• Designed Ankyrin Repeats:

  • Correct RNAP II stalling in repeat disorders

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Conclusion

Abnormal RNA transcription drives disease through four core mechanisms:

1. Initiation Dysregulation: TF/coactivator mutations in cancer

2. Elongation Defects: RNAP II stalling in neurodegeneration

3. Epigenetic Silencing: Cohesinopathies and developmental disorders

4. Termination Failure: Toxic readthrough in repeat expansion diseases

These disruptions create diagnostic biomarkers (eRNA, tRNA fragments) and therapeutic targets (BET/CDK9 inhibitors). Current clinical data shows >75% response rates in transcription-targeted therapies for resistant cancers, with emerging CRISPR and chaperone technologies poised to address neurological and genetic disorders.

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Data sourced from public references. For academic collaboration or content inquiries: chuanchuan810@gmail.com