Abstract

Myeloid ecotropic virus insertion site 1 (MEIS1) is a transcription factor involved in a myriad of functions such as hematopoiesis, cardiac regeneration, cell cycle progression, cell proliferation, and limb and organ development. Precise control of MEIS1 expression and function is essential for maintaining cellular homeostasis and preventing pathological conditions including cancer. Emerging evidence suggests that non-coding RNAs (ncRNAs) play a significant role in fine-tuning MEIS1 activity. Unmasking these regulatory mechanisms could provide potential therapeutic strategies for conditions where MEIS1 is aberrantly expressed. The present dissertation presents a comprehensive overview of current knowledge on MEIS1, synthesizing findings from the literature to highlight its functional versatility and its implications in crucial functions such as carcinogenesis, proliferation, differentiation, cardiovascular regeneration, cell cycle arrest, maintenance of hematopoiesis, and organ patterning and development. This thesis also explores the regulation of MEIS1 at the transcriptional, post transcriptional, and post-translational levels, with particular attention to its complex interactions with the non-coding transcriptome. Building on this foundation, this work presents our experimental approach to explore novel regulatory mechanisms that may influence Meis1 expression and function, with a particular focus on microRNAs (miRNAs/miRs) and long non-coding RNAs (lncRNAs). Using in-silico analysis, miR-499-5p was predicted to target Meis1, and Malat1 was predicted and previously proven to sponge miR-499-5p. For the first time, we showed that forcing the expression of miR-499-5p downregulates Meis1 messenger RNA (mRNA) and protein in C166 cells by directly binding to its 3’UTR. Moreover, Malat1 knockdown significantly increases miR-499-5p expression, subsequently suppressing Meis1. Furthermore, through BrdU proliferation assay, we showed that the knockdown of Malat1, Meis1, or mimicking the expression of miR-499-5p promoted cell proliferation. Gene Ontology, KEGG and Reactome enrichment analyses on proteins identified via mass spectrometry after manipulating Malat1, miR-499-5p, or Meis1 revealed a multitude of differentially expressed proteins related to cell cycle, cell division, and key pathways like Wnt and mTOR, essential for cell proliferation. Finally, since Malat1 and miR 499-5p are conserved in humans and mice, we examined the expression pattern of both ncRNAs in neonatal, postnatal, and adult mice hearts, representing models of proliferative and non-proliferative tissues. We highlighted a paradoxical pattern, where Malat1 is underexpressed while miR-499-5p is overexpressed in proliferative neonatal cardiomyocytes. Collectively, our experimental findings confirm that Malat1 sponges miR-499-5p, regulating Meis1, and that Malat1/miR-499-5p/Meis1 could potentially form an axis that has a pivotal influence on cellular proliferation. Lastly, this thesis highlights the therapeutic potential of modulating MEIS1 activity by presenting current strategies and available pharmacological molecules that target MEIS1. Particular emphasis is placed on RNA-based therapies, such as antisense oligonucleotides (ASO), Locked Nucleic Acid (LNA) gapmers, and miRNA inhibitors, which represent promising tools for future therapeutic applications and warrant further investigation.

School

School of Sciences and Engineering

Department

Biotechnology Program

Degree Name

PhD in Applied Sciences

Graduation Date

Winter 12-18-2025

Submission Date

7-26-2025

First Advisor

Ahmed Abdellatif

Second Advisor

Ahmed Ihab Abdelaziz

Committee Member 1

Ahmed Mostafa

Committee Member 2

Andreas Kakarougkas

Committee Member 3

Hatem Azim

Extent

81 p.

Document Type

Doctoral Dissertation

Institutional Review Board (IRB) Approval

Not necessary for this item

Additional Files
Salma Fahim - IRB form.pdf (73 kB)
IRB approval form- Salma Fahim
Salma Fahim Turnitin.pdf (50 kB)
Turnitin receipt- Salma Fahim
Salma Fahim - Approval page.pdf (38 kB)
Signature page- Salma Fahim
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Available for download on Sunday, January 25, 2026

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