The risk variations and genetic mutations that influence complex neuropsychiatric diseases such as schizophrenia and bipolar disorder often lie within the non-coding regions of the genome. The Computational Neuroepigenomics Group, under the direction of Kiran Girdhar, PhD, investigates how domains of physically interacting regulatory elements affect molecular processes that drive gene expression for neuropsychiatric diseases.
Deciphering the Non-Coding Genome
The function of the non-coding part of the genome has been difficult to unravel. It is estimated that only one percent of the human genome sequence has a coding function, while approximately 25 percent is involved in a regulatory capacity. For schizophrenia and other related psychiatric diseases, up to 90 percent of the genetic risk sequences are located in these regulatory domains. Through analyses of large-scale omics data, our group seeks to identify the mechanisms through which regulatory sequences in the human genome activate or inhibit the expression of genes in specific cell types and stages of neurodevelopment. Our hope is that in the future, we will provide precision medicine the ability to modify these sequences and reduce the prevalence of neuropsychiatric diseases.
Constructing the 3-Dimensional Genome for Neuropsychiatric Diseases
With the linear genome, we have been able to determine through sequencing assays which genes are expressed in neuropsychiatric diseases compared to healthy controls. Our group is building on that knowledge by developing and utilizing computational methods to interpret the three-dimensional genome and its spatial organization within the cell. The center of the nucleus is the most active part of the genome, where proteins are formed. It is important to understand whether the diseased portion of the genome is on the periphery of the nucleus and suppressed, or actively contributing to the molecular processes of the cell.
Our analytical methods integrate epigenomics and transcriptomics data with genetics from the human postmortem brains to test different hypotheses. Our team is leveraging population scale epigenomics data (ChIP-Seq, ATAC-seq, and single-cell ATACseq) to generate architectural units of three-dimensional genomes at different developmental stages, cell types, and brain regions. By correlating nucleosomal histone modifications, open chromatin status, and the Hi-C chromosomal conformation landscape, we are pioneering a higher level of resolution in fine-mapping chromosomal domains for neuropsychiatric diseases.
Identifying the Role of Non-Coding RNA in Neuropsychiatric Diseases
In the human genome, only 3 percent of genetic material has the capability of encoding protein from RNA. The remaining 97 percent of transcribed RNAs are non-coding RNA (ncRNAs), which constitute microRNAs, transfer RNA-derived fragments, ribosomal RNA-derived fragments, enhancer RNAs, and long non-coding RNAs. There is increasing evidence that suggests ncRNAs, specifically miRNAs, are actively involved during neurodevelopmental stages and might play a role in schizophrenia. We are striving to test the hypothesis that SCZ emerges from changes in the expression of an interconnected regulatory network of miRNA and mRNA transcripts during the early developmental stages. Ultimately, we are striving to have a complete understanding of the molecular mechanisms of the genome for neuropsychiatric diseases.