Mechanisms of transcription and translation dysfunction in disease: a novel FMRP-translation axis in Alzheimer’s and expansion of Pol III transcription in cancer

Lizarazo Chaparro, Simon

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https://hdl.handle.net/2142/132515 Copy

Description

Title

Mechanisms of transcription and translation dysfunction in disease: a novel FMRP-translation axis in Alzheimer’s and expansion of Pol III transcription in cancer

Author(s)

Lizarazo Chaparro, Simon

Issue Date

2025-12-01

Director of Research (if dissertation) or Advisor (if thesis)

• Tsai, Nien Pei
• Van Bortle, Kevin

Doctoral Committee Chair(s)

Tsai, Nien Pei

Committee Member(s)

• Chung, Hee Jung
• Zhao, Dave Sihao

Department of Study

Molecular & Integrative Physl

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• RNA Polymerase III
• Cancer
• Functional Genomics
• Alzheimer's Disease
• FMRP
• Bioinformatics
• Neurobiology

Abstract

Gene regulation operates across multiple layers, from chromatin state to RNA processing and translation. Crucially, a gene encodes an RNA molecule before it ever becomes a protein, and RNAs themselves are diverse in form and function. Dysregulation of RNA pathways is implicated in many diseases, like cancer, neurological and immunological disorders, and cardiovascular disease. This dissertation examines RNA biology from complementary angles spanning mechanism, genomics, and methods. Chapter 1 provides a brief overview of RNA biology, emphasizing that RNAs are not merely intermediates in carrying DNA information but active regulators. It surveys regulatory mechanisms at the DNA, transcriptional, and translational levels to frame the chapters that follow. Chapter 2 investigates translational control in an in vitro Alzheimer’s disease model, focusing on the RNA-binding protein Fragile X Messenger Ribonucleoprotein (FMRP). I describe a previously unrecognized mechanism by which FMRP modulates translation under amyloid-β induces toxicity, proposing FMRP as one of several factors that could influence and contribute with AD progression. Chapter 3 turns to large-scale analysis and introduces, the first multi-tissue and tumor atlas of RNA polymerase III (Pol III) transcribed genes accessibility. By integrating more than 500 ATAC-seq datasets, I address the challenges in assaying short, highly similar Pol III transcripts. The atlas resolves housekeeping, tissue-specific, and cancer-emergent Pol III gene sets and proposes regulatory features that may explain the observed context specificity. Motivated by the analytical hurdles encountered in these studies, Chapter 4 presents dominatR, an R package for visualizing feature dominance across contexts. The tool interoperates with the Bioconductor ecosystem and is released as a publicly available resource. Chapter 5 synthesizes the main findings, outlines limitations of the experimental and computational approaches, and proposes concrete directions for future work. Together, these studies expand our understanding of RNA-centered regulation across molecular layers and disease contexts, combining mechanistic insight, atlas-scale genomics, and open-source tools.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132515

Copyright and License Information

Copyright 2025 Simon Lizarazo Chaparro

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