Pioneer factor Pax7 initiates two-step cell-cycle-dependent chromatin opening

Area of Science:

• Molecular Biology
• Epigenetics
• Cell Biology

Background:

• Pioneer transcription factors are crucial for cell differentiation, initiating chromatin remodeling.
• The precise sequence of events in pioneer factor action, particularly Pax7, remains unclear.
• Pioneers interact with DNA and chromatin remodelers, but initial steps are undefined.

Purpose of the Study:

• To define the sequential events underlying pioneer transcription factor Pax7's chromatin remodeling and cell differentiation capabilities.
• To elucidate the role of chromatin condensation and histone modifications in early pioneer factor recruitment.
• To investigate the necessity of cell division and nuclear compartment dynamics for subsequent remodeling steps.

Main Methods:

• Investigated the interaction of pioneer factor Pax7 with chromatin.
• Analyzed the role of linker histone H1 in chromatin condensation and Pax7 recruitment.
• Examined the recruitment of KDM1A (LSD1) and MLL complexes for histone mark deposition.
• Assessed the impact of cell division and dissociation from lamin B on SWI-SNF and p300 recruitment.
• Studied enhancer activation following nucleosome displacement.

Main Results:

• Linker histone H1-mediated chromatin condensation is the initial constraint on Pax7 recruitment, setting the pace for remodeling.
• Pioneer action involves recruiting KDM1A (LSD1) to remove H3K9me2 and the MLL complex to deposit H3K4me1.
• Progression requires cell division and dissociation from perinuclear lamin B, enabling SWI-SNF and p300 recruitment.
• Nucleosome displacement and enhancer activation occur after these sequential events within the lamin-associated nuclear compartment.

Conclusions:

• Pioneer transcription factors like Pax7 orchestrate cell differentiation through a defined sequence of chromatin remodeling events.
• Initial steps involve histone modification recruitment, while later stages depend on cell division and nuclear repositioning.
• The lamin-associated nuclear compartment plays a unique role in enabling the full spectrum of pioneer factor-driven enhancer activation.