Multiomic profiling of transcription factor binding and function in human brain.

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Transcription factors (TFs) are vital for brain function, but their binding patterns in human brain tissue are not well understood.
• Detailed information on TF binding is crucial for deciphering gene expression regulation in the brain.

Purpose of the Study:

• To create a comprehensive multiomic resource (BrainTF) detailing transcription factor binding in the human brain.
• To improve the measurement and modeling of TF activity and binding.
• To investigate the role of specific TFs in neuronal gene expression and their association with neuropsychiatric disorders.

Main Methods:

• Generation of a multiomic dataset including ChIP-seq, ATAC-seq, RNA-seq, and DNA methylation from postmortem human brain tissues.
• Analysis of over 100 transcription factors' binding maps.
• Development of improved TF activity measurements and predictive binding models.
• Identification and removal of high TF occupancy regions to refine analyses.

Main Results:

• Creation of a rich resource with binding maps for over 100 TFs across multiple brain regions.
• Demonstration of enhanced TF activity measurements and gene expression modeling after accounting for high occupancy sites.
• Identification of neuronal TFs SATB2 and TBR1 binding unique regions and promoting neuronal gene expression.
• Enrichment of TF binding sites (TBR1, PKNOX1) with neuropsychiatric disorder risk variants, primarily in neurons.

Conclusions:

• The BrainTF resource provides unprecedented insights into TF binding and function in the human brain.
• Understanding TF binding patterns is critical for elucidating gene regulation in neurological processes and diseases.
• This resource will facilitate future research into the specific roles of TFs in brain function and neuropsychiatric disorders.