Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• The CCCTC-binding factor (CTCF) and cohesin complex are crucial for chromatin loop and topologically associating domain formation.
• The precise role of CTCF in gene regulation, particularly during cellular differentiation, remains incompletely understood.

Purpose of the Study:

• To investigate the impact of acute CTCF loss on chromatin architecture and transcriptional programs during mouse embryonic stem cell differentiation into neural precursor cells.
• To identify CTCF-dependent enhancer-promoter contacts and their influence on gene regulation.

Main Methods:

• Investigated CTCF loss effects in differentiating mouse embryonic stem cells.
• Performed genome-wide identification of CTCF-dependent enhancer-promoter contacts.
• Assessed transcriptional changes upon CTCF disruption and restoration via artificial tethering.

Main Results:

• CTCF-dependent enhancer-promoter contacts were identified genome-wide.
• Disruption of promoter-proximal CTCF binding impaired long-range enhancer-promoter contacts and gene transcription.
• Artificial tethering of CTCF to promoters restored enhancer-promoter contacts and transcription.
• Promoter-proximal CTCF binding correlates with transcription of over 2,000 genes across various adult tissues.

Conclusions:

• CTCF binding at promoters is essential for maintaining long-distance enhancer-promoter contacts.
• CTCF plays a critical role in regulating transcription of specific genes, particularly those reliant on long-distance enhancers.
• Promoter-proximal CTCF binding facilitates enhancer-dependent transcription in diverse cell types.