Pre-existing chromatin accessibility of switchable repressive compartment delineates cell plasticity

Area of Science:

• Epigenetics and chromatin biology
• Cellular reprogramming and differentiation
• Genomics and gene regulation

Background:

• Cell plasticity enables differentiated cells to change lineage, but intrinsic epigenetic factors remain unclear.
• Extrinsic factors influencing cell identity conversion are known, yet the role of chromatin organization is elusive.

Purpose of the Study:

• To identify intrinsic epigenetic attributes, specifically high-order chromatin organization, that define cell plasticity.
• To investigate the role of unique chromatin units in transcription-factor-induced cell transdifferentiation.

Main Methods:

• Analysis of transcription-factor-induced transdifferentiation from fibroblasts to hepatocytes.
• Identification and characterization of contiguous compartment-switchable regions (CSRs).
• Investigation of chromatin accessibility, epigenetic modifications, and gene expression within CSRs, with CTCF occupancy analysis.

Main Results:

• Discovered contiguous compartment-switchable regions (CSRs) as a novel chromatin unit governing cell plasticity.
• Compartment B-to-A CSRs in fibroblasts showed a mosaic status with pre-existing accessibility, facilitating hepatic gene enrichment.
• Pre-existing accessibility in CSRs enhanced transcription factor binding (Foxa3), triggering epigenetic activation, chromatin interaction, and gene expression within CTCF-defined boundaries.

Conclusions:

• CSRs represent a fundamental chromatin unit that delineates cell plasticity and facilitates lineage conversion.
• The mosaic chromatin status and pre-existing accessibility within CSRs are critical intrinsic epigenetic attributes for cell reprogramming.
• CTCF-defined CSR boundaries constrain epigenetic changes, highlighting their role in maintaining cellular identity and plasticity across different cell types.