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PsycENCODE: Exploring the Function of Non-coding Elements in the Brain

NAMHC Concept Clearance

Presenter

Patrick Bender, Ph.D.
Genomics Research Branch
Division of Neuroscience and Basic Behavioral Science (DNBBS)

Goal

This initiative aims to support studies on mental disorders based on new concepts of transcriptome complexity that assign functional roles to non-coding and potentially novel coding transcripts, exploring their potential as trans-regulators of gene transcription, mRNA splicing, mRNA stability, molecular transport, and influence on chromosome architecture.

Rationale

The completion of the human genome sequence was a watershed event in understanding human biology and has led to a plethora of new insights into the complexity and structure of the genome. One of the most striking findings was the relatively small number of protein coding sequences relative to the size of the genome and the resulting obvious question: what is the rest of the genome for? Results from the ENCODE and modENCODE projects  and the brain transcriptional atlas indicate that significant portions of the genome, beyond the known RefSeq coding sequences, are highly conserved, and much of the conserved sequence gives rise to transcripts of unknown function (TUFs). These TUFs include non-polyadenylated and non-ribosomal RNAs as well as polyadenylated transcripts with potential regulatory roles. They arise from intergenic and intragenic (introns and 3’/5’ nontranlated) regions as well as psuedogenes and potential coding sequences from unannotated genes. TUFs include such designations as hetero-nuclear RNA, micro-RNA, and small nuclear-RNA. Our understanding of how these transcripts impact function, potentially contributing to disease phenotypes, is at an early stage. However, some TUFs exhibit developmental and spatial specificity in their expression profiles suggesting functional roles in tissue phenotype.

Areas of interest include but are not limited to:

  • Quantifying and chromosome mapping transcriptional activities of non-coding DNA;
  • Mapping genotype variants to non-coding TUFs;
  • Mapping findings from genome-wide association and sequencing studies in mental disorders to regions of TUF sequence;
  • Comparing abundance and species of TUFs from different regions of the brain to other tissues to identify tissue specificity;
  • Using model systems for comparative analyses and to explore functional outcomes;
  • Using systems approaches to define gene-networks that include TUFs;
  • Identifying trans-effects of TUFs on other mRNA transcripts, including abundance, splice variants, and allele-specific expression;
  • Comparing TUFs’ expression in tissues from healthy controls to those in individuals with mental disorders; and
  • Employing model systems and computational approaches to delineate the role of evolutionarily constrained non-protein coding sequences.

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