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Thesis Format



Master of Science




Berube, Nathalie G.


TRIM28 is a developmental chromatin regulator. It influences pluripotency and preserves genomic integrity by suppressing transposable elements (TEs). A TRIM28 variant (T2123C) was recently identified in a pediatric patient with a neurodevelopmental disorder. Human induced pluripotent stem cells (iPSCs) harboring this variant were generated to investigate potential pathogenic outcomes. We found that the T2123C variant does not affect TRIM28 transcript or protein levels or its nuclear localization. However, the morphology of mutant cells appeared to be affected, and the compactness of colonies was reduced. Although expression of core pluripotency factors did not differ, transcriptome analysis unveiled alteration of neural development-related genes, suggesting priming of mutant iPSCs to a neural fate. Moreover, this mutation led to the de-repression of all TE families. Overall, this study revealed that the T2123C TRIM28 variant causes TE activation, dysregulation of iPSC morphology and premature expression of neural lineage genes without affecting core pluripotency factors.

Summary for Lay Audience

Here, we studied a random change in the TRIM28 gene found in a child patient with a neurodevelopmental disorder. The TRIM28 gene produces a protein that plays an important role during development. TRIM28 protein recruits a group of silencer proteins to DNA, preventing specific genes from giving instructions. TRIM28 and its partners also block jumping elements in our DNA. Jumping elements are groups of elements that can move around or interfere with instructions of various genes leading to miscommunications. TRIM28 is highly produced in embryonic stem cells (ESCs). ESCs are cells residing in the human embryo with the unique ability to become different cell types. Under precise instructions at the right time, these cells undergo transformations, leading to the formation of diverse organs in the human body. The high potential state of these cells is controlled by many proteins, including SOX2, NANOG, and OCT4. TRIM28 is also involved in regulating this high potential state. Here, we explored the effect of this change in the TRIM28 gene using a human stem cell model resembling ESCs. We found that this change did not affect the level of the TRIM28 protein in these cells, nor did it affect levels of the SOX2, NANOG and OCT4 proteins. However, we discovered that genes involved in the development of nervous system cells were abnormally activated. Additionally, we found that jumping elements were no longer silenced, suggesting disturbance and miscommunications caused by these elements. Overall, our findings demonstrate that the change identified in the TRIM28 gene in the affected patient leads to abnormal function without affecting protein levels, suggesting that it is causing the observed clinical manifestations.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

Available for download on Sunday, March 08, 2026