Endothelial cell differentiation is encompassed by changes in long range interactions between inactive chromatin...

Area of Science:

• Cell Biology
• Genomics
• Developmental Biology

Background:

• Endothelial cells (ECs) are crucial for blood vessel formation, originating from mesodermal progenitors.
• Understanding the dynamic changes in chromatin organization during EC differentiation is key to deciphering vascular development.

Purpose of the Study:

• To investigate the genome-wide chromatin interaction changes during endothelial cell differentiation.
• To identify endothelial cell-specific chromatin structures and their regulatory elements.
• To explore the impact of hypoxia on endothelial cell chromatin organization.

Main Methods:

• Comparative analysis of chromatin interactions using Hi-C in human umbilical vein ECs, embryonic stem cells, and mesendoderm cells.
• Identification and characterization of endothelial cell-specific topologically associated domains (TADs) and long-range interactions (LRIs).
• Assessment of gene expression and transcription factor binding, including HIF1α, under normoxic and hypoxic conditions.

Main Results:

• Identified EC-specific compartmentalization and altered connectivity within TADs, associated with EC transcription factors and cohesin.
• Discovered 1200 EC-specific LRIs, many involving H3K9me3-enriched pericentromeric regions, suggesting heterochromatin organization.
• Observed that hypoxia minimally affects overall chromatin organization, with hypoxia-inducible genes primarily located within pre-established HIF1α-bound TADs.

Conclusions:

• Large-scale chromatin rearrangements establish the architecture essential for endothelial cell function.
• The established endothelial chromatin architecture is largely resistant to hypoxic stress.
• Transcriptional responses to hypoxia are predominantly mediated through pre-existing chromatin organization patterns.