ERRα induces H3K9 demethylation by LSD1 to promote cell invasion

Area of Science:

• Epigenetics
• Molecular Biology
• Cell Biology

Background:

• Lysine Specific Demethylase 1 (LSD1) is a histone demethylase with dual functions, catalyzing both gene repression and activation.
• The precise mechanisms governing LSD1's switch between these antagonistic activities remain largely unknown.
• Estrogen-related receptor α (ERRα) is an orphan nuclear receptor with roles in various cellular processes.

Purpose of the Study:

• To elucidate the regulatory mechanisms controlling LSD1's dual biochemical activities.
• To investigate the interplay between LSD1 and ERRα in gene regulation.
• To determine the functional significance of LSD1-ERRα co-regulation in cellular processes like cell migration.

Main Methods:

• Chromatin immunoprecipitation (ChIP) assays to assess histone modifications at target gene promoters.
• In vitro demethylase assays to evaluate LSD1 activity in the presence of ERRα.
• Gene expression analysis (e.g., qRT-PCR, Western blot) to quantify target gene levels.
• Cellular invasion assays (e.g., Matrigel invasion) to assess migratory capacity.
• Gene depletion studies (e.g., siRNA, shRNA) to evaluate the roles of LSD1 and ERRα.

Main Results:

• LSD1 and ERRα share commonly activated target genes, indicating co-regulation.
• Transcriptional activation by LSD1 and ERRα is associated with H3K9 demethylation at the transcriptional start site (TSS).
• ERRα directly induces LSD1 to demethylate H3K9 in vitro, suggesting a mechanism for switching LSD1 activity.
• LSD1 and ERRα co-regulate MMP1, a key matrix metallo-protease involved in cell migration.
• Depletion of LSD1 or ERRα impairs extracellular matrix invasion, which can be rescued by MMP1 reexpression.

Conclusions:

• ERRα acts as a direct regulator of LSD1, switching its function towards gene activation.
• This epigenetic regulatory network, involving LSD1's biochemical activity switch, promotes cell invasion.
• The LSD1-ERRα-MMP1 axis represents a novel regulatory pathway controlling cell migration and extracellular matrix remodeling.