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Deep-Learning Uncovers certain CCM Isoforms as Transcription Factors
Jacob Croft1, Liyuan Gao2, Victor Sheng2
1Department of Molecular & Translational Medicine (MTM), Texas Tech University Health Science Center El Paso (TTUHSCEP), El Paso, TX 79905, USA.
Frontiers in Bioscience (Landmark Edition)
|February 29, 2024
Summary
Cerebral Cavernous Malformation proteins (CCMs) can act as transcription factors, regulating gene expression. This study identified 8 CCM isoforms with this novel function, challenging existing research.
Area of Science:
- Molecular biology
- Genetics
- Bioinformatics
Background:
- Cerebral Cavernous Malformations (CCMs) are vascular abnormalities linked to stroke risk.
- Familial CCMs involve KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) genes.
- CCM proteins shuttle between nucleus and cytoplasm, suggesting roles in gene regulation.
Purpose of the Study:
- To investigate if CCM proteins function as transcription factors (TFs).
- To identify specific CCM isoforms with TF capabilities.
Main Methods:
- Utilized a deep-learning (DL) algorithm with a biased-Support Vector Machine (SVM) model.
- Analyzed CCM gene isoforms exhibiting nucleocytoplasmic shuttling.
Main Results:
- Identified 11 CCM isoforms across CCM1, CCM2, and CCM3.
- Confirmed transcription factor functionality in 8 CCM1 and CCM2 isoforms.
- This is the first identification of CCM isoforms acting as TFs.
Conclusions:
- CCM proteins possess dual roles, acting as both signaling components and transcription factors.
- This finding expands the known functions of CCM proteins beyond endothelial cell signaling.
- Challenges the established view of CCMs solely in angiogenesis-related signaling cascades.
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