Cellular reprogramming is driven by widespread rewiring of promoter-enhancer interactions

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Long-range interactions between gene promoters and cis-regulatory elements are crucial for gene regulation.
• The role of three-dimensional (3D) chromatin structure in direct cell reprogramming remains unclear.

Purpose of the Study:

• To investigate the impact of 3D chromatin structure on transcriptional regulation during direct cell reprogramming.
• To analyze changes in chromosomal architecture, epigenetics, and gene expression during Pre-B cell to macrophage trans-differentiation.

Main Methods:

• Integrated analyses using Hi-C, promoter Capture Hi-C (PCHi-C), ChIP-seq, and RNA-seq.
• Utilized a β-estradiol inducible C/EBPαER transgene for trans-differentiation of Pre-B cells into macrophages.

Main Results:

• C/EBPα induction rapidly altered gene expression, downregulating Pre-B cell genes and upregulating macrophage genes.
• Genome architecture showed minimal changes in TAD boundaries and A/B compartments.
• Promoter Capture Hi-C revealed widespread changes in promoter-anchored loops correlating with gene expression changes.

Conclusions:

• C/EBPα-induced trans-differentiation involves limited alterations in TADs and A/B compartments.
• Significant reorganization of promoter-anchored loops accompanies changes in gene expression and cell identity during reprogramming.