Theses Doctoral

Exploring a non-canonical mode of gene regulation mediated by mRNA transcript isoform switching in the context of mammalian development

Keskin, Abdurrahman

Long undecoded transcript isoforms (LUTIs) are a class of non-canonical mRNAs that repress gene expression by a combined mechanism of transcriptional and translational interference. Although this mechanism has been shown to be widespread in yeast, its prevalence in mammals has not been established.

Using human embryonic stem cells (hESCs) differentiated into endoderm, mesoderm, and ectoderm lineages and further differentiation into polyhormonal cells, cardiomyocytes, and motor neurons, respectively, we obtained a comprehensive dataset through mRNA-seq, ribosome profiling, and quantitative mass spectrometry measurements. Our analysis revealed that LUTI-based regulation is context-dependent, with a total of 271 genes identified in ectoderm to motor neuron differentiation, 69 genes in mesoderm to cardiomyocyte differentiation, and 99 genes in endoderm to polyhormonal cell differentiation. Translational repression of LUTI candidates was found to be primarily dependent on upstream open reading frames (uORFs), while LUTI-based transcriptional repression displayed variability.

This study enhances our understanding of gene expression and regulation during mammalian development and highlights the potential significance of LUTI-based regulation in the development of specific cell types or tissues. The findings lay the groundwork for further exploration into the role of LUTI- based regulation in other mammalian developmental programs and its potential implications for therapeutic targets in developmental disorders and diseases.


This item is currently under embargo. It will be available starting 2025-07-10.

More About This Work

Academic Units
Biological Sciences
Thesis Advisors
Jovanovic, Marko
Ph.D., Columbia University
Published Here
July 12, 2023