Chromatin interaction maps identify Wnt responsive cis-regulatory elements coordinating Paupar-Pax6 expression in...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Long non-coding RNAs (lncRNAs) in the central nervous system are often located near protein-coding genes involved in transcriptional control.
• Co-expression of neighboring lncRNA-protein coding gene pairs is common in the nervous system, suggesting coordinated roles in neuronal development and function.
• The precise regulatory mechanisms governing the co-expression of these adjacent genes remain largely unknown.

Purpose of the Study:

• To investigate the cis-regulatory interaction landscape of the neuro-developmental Paupar-Pax6 lncRNA-mRNA locus using high-resolution NG Capture-C.
• To understand the chromatin architecture changes and regulatory elements involved in the co-expression of Paupar and Pax6 in neurons.
• To identify transcription factors that coordinate the co-expression of Paupar and Pax6.

Main Methods:

• High-resolution NG Capture-C was employed to map cis-regulatory interactions.
• Analysis of chromatin architecture changes associated with Paupar-Pax6 expression.
• Identification of transcription factor binding sites and their role in gene co-regulation.

Main Results:

• Defined the chromatin architecture changes linked to high Paupar-Pax6 expression in neurons.
• Identified both shared and promoter-selective cis-regulatory interactions governing Paupar-Pax6 co-expression.
• Discovered that the TCF7L2 transcription factor binds to specific cis-regulatory elements, coordinating Paupar and Pax6 co-expression.
• Revealed distinct roles for Paupar in Pax6 expression control, with its DNA locus containing a TCF7L2-bound silencer and the transcript acting as a Pax6 activator.

Conclusions:

• Provides crucial insights into the chromatin interactions, signaling pathways (Wnt pathway), and transcription factors controlling the co-expression of adjacent lncRNAs and protein-coding genes in the brain.
• Highlights the role of TCF7L2 in orchestrating the coordinated expression of lncRNA-mRNA pairs.
• Elucidates the dual function of the Paupar transcript and its locus in regulating Pax6 expression.