Two distinct chromatin modules regulate proinflammatory gene expression

Area of Science:

• Genomics
• Molecular Biology
• Cell Biology

Background:

• Gene activation involves mechanisms like enhancer-promoter interactions and transcription factor hubs.
• Genome-wide studies on distinct endogenous gene regulation mechanisms in primary human cells are limited.

Purpose of the Study:

• To investigate mechanistic differences in gene regulation within primary human endothelial cells.
• To dissect the proinflammatory gene expression program induced by tumor necrosis factor (TNF).

Main Methods:

• Utilized sequencing- and imaging-based methods for comprehensive analysis.
• Employed co-accessibility analysis of single-cell chromatin accessibility data.
• Developed and used the RWireX software for data analysis.

Main Results:

• Identified two distinct regulatory chromatin modules: autonomous links of co-accessibility (ACs) and domains of contiguous co-accessibility (DCs).
• ACs involve co-accessibility between separated genomic sites, while DCs feature contiguous co-accessibility with increased local transcription factor binding.
• Observed differential TNF-dependent induction timing, strength, and transcriptional bursting kinetics for genes in AC and DC modules.

Conclusions:

• The study reveals functionally distinct regulatory mechanisms associated with ACs and DCs.
• These findings offer a framework for understanding rapid and precise gene expression control in cells.
• Highlights the importance of distinct chromatin structures in orchestrating cellular responses.