Global Genome Conformational Programming during Neuronal Development Is Associated with CTCF and Nuclear FGFR1-The...

Area of Science:

• Genomics
• Developmental Biology
• Epigenetics

Background:

• Mouse embryonic stem cells (ESC) differentiate into neuronal committed cells (NCC) through complex gene expression changes.
• Nuclear FGFR1 (nFGFR1) plays a role in regulating gene expression during this differentiation process.

Purpose of the Study:

• To investigate genome-wide changes in chromosomal interactions and Topologically Associating Domains (TADs) during ESC to NCC differentiation.
• To understand the role of nFGFR1 in mediating these structural genome changes and their impact on gene regulation and cell fate.

Main Methods:

• Genome-wide analysis of inter- and intra-chromosomal interactions and chromatin looping.
• Identification and characterization of CTCF- and nFGFR1-linked TADs.
• Experimental disruption of FGFR1 signaling to assess its impact on loop formation.
• Correlation analysis between nFGFR1 binding, genome interactions, and gene expression.

Main Results:

• Significant differences in chromosomal interactions and TAD formation were observed between ESCs and NCCs.
• Blocking FGFR1 disrupted chromatin loop formation, particularly within the HoxA cluster.
• FGFR1 binding sites and genome interactions were predictive of genome function and gene expression.
• A topologically integrated genome archipelago model was proposed, highlighting nFGFR1-associated TADs in developmental programs.

Conclusions:

• nFGFR1 is a key mediator of genome structural reorganization during ESC to NCC differentiation.
• The formation and transformation of nFGFR1-associated TADs are crucial for recruiting specific ontogenic programs.
• This study provides insights into the interplay between genome architecture, gene regulation, and cell fate determination.