ATF3 drives senescence by reconstructing accessible chromatin profiles

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Cellular senescence is a state of irreversible cell cycle arrest.
• Chromatin organization and gene expression change significantly during senescence.
• Regulatory mechanisms linking chromatin changes to gene expression in senescence are not fully understood.

Purpose of the Study:

• To investigate the regulatory mechanisms between chromatin reconstruction and gene expression during human umbilical vein endothelial cell (HUVEC) senescence.
• To map the dynamic landscape of chromatin accessibility and gene expression in senescent HUVECs.

Main Methods:

• Analysis of chromatin accessibility and gene expression profiles in HUVEC senescence.
• Identification of key transcription factors involved in chromatin remodeling.
• Assessment of DNA methylation's role in transcription factor binding.

Main Results:

• Chromatin accessibility is redistributed during HUVEC senescence, with significant shifts in intergenic regions, primarily enhancer elements.
• The AP-1 transcription factor family was identified as a key driver of chromatin accessibility reconstruction.
• Low DNA methylation enhances AP-1 binding affinity, further increasing chromatin accessibility.
• ATF3 was confirmed as a critical AP-1 transcription factor for promoting cellular senescence by reconstructing chromatin accessibility.

Conclusions:

• Chromatin accessibility remodeling is a dynamic process contributing to the cellular senescence program.
• The AP-1 transcription factor family plays a crucial role in reorganizing chromatin accessibility profiles to regulate senescence.
• ATF3 is a key regulator in this process, highlighting a novel mechanism in senescence.