Hooked Up from a Distance: Charting Genome-Wide Long-Range Interaction Maps in Neural Cells Chromatin to Identify...

Area of Science:

• Genomics
• Neuroscience
• Molecular Biology

Background:

• DNA sequence variants, including single nucleotide polymorphisms (SNPs/SNVs) and copy number variants (CNVs), associated with neurodevelopmental disorders (NDD) and traits frequently map to transcriptional regulatory elements like enhancers.
• The genes regulated by these enhancers, particularly in neural development, have remained poorly understood, challenging traditional models that assumed enhancers primarily influence the nearest gene promoter.

Approach:

• This perspective reviews studies utilizing genome-wide long-range interaction maps (e.g., Hi-C, ChIA-PET, Capture-Hi-C, PLAC-seq) generated from neural cells.
• These interaction maps are overlapped with DNA sequence variants linked to NDDs (e.g., schizophrenia, autism, bipolar disorder) and cognitive traits (e.g., intelligence).

Key Points:

• Long-range interaction maps reveal that enhancers often connect to gene promoters located distantly on the linear chromosome, bypassing intervening genes.
• This approach successfully attributed functions of enhancers harboring NDD-associated variants to these distant, connected promoters.
• The identified enhancer-connected genes include previously known disease contributors (validated by exonic mutations) and numerous novel candidate genes not previously linked to NDDs through coding region mutations.

Conclusions:

• Genome-wide long-range interaction maps serve as powerful tools to identify novel candidate genes implicated in neurodevelopmental disorders and traits by linking variants in regulatory elements to their target genes.
• Functional studies using CRISPR-Cas9 are beginning to validate the significance of these enhancer-promoter interactions and their roles in neural development and pathology, offering new avenues for understanding NDDs.