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

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.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Molecular & Integrative Physi

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Lizarazo Chaparro, Simon

Contributors dc:contributor

• Tsai, Nien Pei
• Van Bortle, Kevin
• Chung, Hee Jung
• Zhao, Dave Sihao

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

Statement dc:rights

• Copyright 2025 Simon Lizarazo Chaparro

Language dc:language

en

Handle dc:identifier

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

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/132515