PUBLICATION
Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
- Authors
- Yousefi, S., Deng, R., Lanko, K., Salsench, E.M., Nikoncuk, A., van der Linde, H.C., Perenthaler, E., van Ham, T.J., Mulugeta, E., Barakat, T.S.
- ID
- ZDB-PUB-211022-27
- Date
- 2021
- Source
- Genome Medicine 13: 162 (Journal)
- Registered Authors
- Barakat, Stefan, Salsench, Eva, van der Linde, Herma, van Ham, Tjakko
- Keywords
- Clinical genetics, Computational analysis, Data integration, Enhancer, Epigenome, Gene regulatory elements, Human brain development, Mendelian disorders, Meta-analysis, Non-coding genome
- MeSH Terms
-
- Animals
- Binding Sites
- Brain/growth & development*
- Enhancer Elements, Genetic*
- Epigenomics*
- Gene Expression Regulation, Developmental*
- Genome
- HEK293 Cells
- Humans
- Phenotype
- Pneumonia, Aspiration/genetics
- Transcription Factors
- Zebrafish/genetics
- PubMed
- 34663447 Full text @ Genome Med.
Citation
Yousefi, S., Deng, R., Lanko, K., Salsench, E.M., Nikoncuk, A., van der Linde, H.C., Perenthaler, E., van Ham, T.J., Mulugeta, E., Barakat, T.S. (2021) Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance. Genome Medicine. 13:162.
Abstract
Background Non-coding regulatory elements (NCREs), such as enhancers, play a crucial role in gene regulation, and genetic aberrations in NCREs can lead to human disease, including brain disorders. The human brain is a complex organ that is susceptible to numerous disorders; many of these are caused by genetic changes, but a multitude remain currently unexplained. Understanding NCREs acting during brain development has the potential to shed light on previously unrecognized genetic causes of human brain disease. Despite immense community-wide efforts to understand the role of the non-coding genome and NCREs, annotating functional NCREs remains challenging.
Methods Here we performed an integrative computational analysis of virtually all currently available epigenome data sets related to human fetal brain.
Results Our in-depth analysis unravels 39,709 differentially active enhancers (DAEs) that show dynamic epigenomic rearrangement during early stages of human brain development, indicating likely biological function. Many of these DAEs are linked to clinically relevant genes, and functional validation of selected DAEs in cell models and zebrafish confirms their role in gene regulation. Compared to enhancers without dynamic epigenomic rearrangement, DAEs are subjected to higher sequence constraints in humans, have distinct sequence characteristics and are bound by a distinct transcription factor landscape. DAEs are enriched for GWAS loci for brain-related traits and for genetic variation found in individuals with neurodevelopmental disorders, including autism.
Conclusion This compendium of high-confidence enhancers will assist in deciphering the mechanism behind developmental genetics of human brain and will be relevant to uncover missing heritability in human genetic brain disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping