Two target gene activation pathways for orphan ERR nuclear receptors

Area of Science:

• Molecular Biology
• Gene Regulation
• Nuclear Receptors

Background:

• Estrogen-related receptors (ERRα/β/γ) are orphan nuclear receptors involved in critical physiological processes.
• The precise mechanisms of target gene activation by ERRs remain largely unelucidated.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Estrogen-related receptors (ERRs) activate target gene transcription.
• To investigate the roles of different coactivators and initiation factors in ERR-mediated gene expression.

Main Methods:

• Reconstituted biochemical assays using DNA and chromatin templates.
• Analysis of interactions between ERRs, transcription initiation factors (TFIIH), and coactivators (PGC-1α, p300, MED1, NCOA3).
• Combined genetic and RNA-sequencing (RNA-seq) analyses in embryonic stem cells.

Main Results:

• ERRs activate transcription on DNA templates via direct interaction between the ERR DNA-binding domain and the p52 subunit of TFIIH.
• On chromatin templates, ERR activation depends on AF2 domain interactions with coactivators like PGC-1α, which recruit p300 and MED1/Mediator.
• NCOA3 can act as an alternative coactivator, selectively recruiting Mediator to ERRβ and ERRγ.
• Both TFIIH and AF2-dependent pathways are essential for ERRβ/γ-selective gene expression and pluripotency maintenance in embryonic stem cells, with NCOA3 being critical.

Conclusions:

• Two distinct mechanisms, TFIIH interaction and coactivator recruitment, mediate ERR-dependent transcription.
• These pathways are functionally integrated and essential for maintaining embryonic stem cell pluripotency.
• NCOA3 plays a significant role as a coactivator for ERRβ/γ in stem cell maintenance.