Integrative single‑cell multi‑omics network analysis to elucidate epigenetic regulation in neurodevelopmental...

Area of Science:

• Neuroscience
• Genomics
• Epigenetics

Background:

• Neurodevelopmental disorders (NDDs) stem from disrupted brain formation, with underlying epigenetic and transcriptional mechanisms poorly understood.
• Existing single-cell studies are often unimodal, limiting the resolution of multi-layer molecular dysregulation.

Purpose of the Study:

• To develop and apply an integrative single-cell multi-omics framework for analyzing epigenetic and transcriptional alterations in NDDs.
• To identify cell-type-specific regulatory networks and quantify molecular deviations in NDD-relevant cell populations.

Main Methods:

• Combined single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), and single-cell DNA methylation profiling.
• Employed canonical correlation analysis, manifold alignment, latent-variable modeling, and network inference for integrative analysis.
• Utilized developing human and mouse brain tissue and patient-derived neural progenitor models.

Main Results:

• Identified neural progenitors and excitatory neurons as exhibiting the most significant multimodal alterations in NDDs.
• Observed promoter hypermethylation, reduced enhancer accessibility, and downregulated neurogenic/synaptic pathways.
• SOX11 and CHD8 identified as master regulators implicated in aberrant lineage specification through integrative network modeling.

Conclusions:

• The integrative framework provides a unified view of multi-layer molecular dysregulation in NDDs.
• Generated mechanistic hypotheses for NDDs, highlighting potential for biomarker discovery and therapeutic interventions.
• Demonstrated the framework's accuracy in enhancer-gene linkage, cross-species conservation, and regulatory module reconstruction.