Non-coding structural variants disrupt FOXG1 transcriptional regulation in early neurodevelopment

Area of Science:

• Genetics
• Developmental Biology
• Neuroscience

Background:

• FOXG1 is vital for embryonic brain development, and its variants cause FOXG1 syndrome.
• Non-coding structural variants downstream of FOXG1 are linked to similar conditions, but their regulatory mechanisms are unclear.

Purpose of the Study:

• To identify and characterize non-coding regulatory variants and elements impacting FOXG1 transcription.
• To understand the pathomechanisms underlying FOXG1 syndrome-like features caused by structural variants.

Main Methods:

• Identification of non-coding structural variants in affected individuals.
• Epigenomic profiling to map regulatory elements.
• In vivo enhancer assays to validate regulatory function.
• Analysis of gene expression and cellular population shifts.

Main Results:

• Delineation of a ~124kb commonly affected regulatory region downstream of FOXG1.
• Characterization of novel enhancer clusters and progenitor-specific enhancers crucial for forebrain development.
• Demonstration that perturbation of these elements reduces FOXG1 transcription and alters neural progenitor cell populations.
• Identification of aberrant PRKD1 expression upon removal of a TAD boundary.

Conclusions:

• Characterization of essential enhancer and architectural elements for FOXG1 regulation during neurodevelopment.
• Provides insights into the regulatory pathomechanisms of FOXG1 syndrome.
• Improves the interpretation of non-coding variants in the FOXG1 locus for clinical diagnostics.