Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition.

Area of Science:

• Cellular plasticity
• Epigenetics
• Cancer biology

Background:

• Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process implicated in development, repair, and cancer progression.
• While epigenetic reprogramming is known in stem cell differentiation and cancer, EMT-specific epigenetic changes remain largely uncharacterized.

Purpose of the Study:

• To investigate epigenetic modifications occurring during transforming growth factor beta-induced EMT.
• To identify the role of specific epigenetic regulators, such as lysine-specific demethylase-1 (Lsd1), in EMT-associated epigenetic reprogramming.

Main Methods:

• Analysis of DNA methylation and histone modifications (H3K9Me2, H3K4Me3, H3K36Me3) during EMT.
• Functional studies involving loss of Lsd1 function to assess its impact on EMT.
• Genome-wide mapping of chromatin changes, focusing on large organized heterochromatin K9 modifications (LOCKs).

Main Results:

• DNA methylation remained unchanged during EMT.
• A global decrease in H3K9Me2 (heterochromatin) and increases in H3K4Me3 (euchromatin) and H3K36Me3 (transcription) were observed.
• These epigenetic alterations were largely dependent on Lsd1, and its inhibition significantly affected EMT-driven cell migration and chemoresistance.
• Chromatin changes were predominantly localized to LOCKs, indicating domain-specific reprogramming.

Conclusions:

• EMT is characterized by significant, domain-specific epigenetic reprogramming, particularly involving histone modifications.
• Lsd1 plays a critical role in mediating these epigenetic changes and influencing key EMT-associated cellular behaviors like migration and chemoresistance.
• Understanding these EMT-related epigenetic dynamics offers potential therapeutic targets for cancer treatment.