Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance

Soheil Yousefi, Ruizhi Deng, Kristina Lanko, Eva Medico Salsench, Anita Nikoncuk, Herma C. van der Linde, Elena Perenthaler, Tjakko J. van Ham, Eskeatnaf Mulugeta, Tahsin Stefan Barakat*

*Corresponding author for this work

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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.

Original languageEnglish
Article number162
JournalGenome Medicine
Volume13
Issue number1
Early online date19 Oct 2021
DOIs
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
RD is supported by a China Scholarship Council (CSC) PhD Fellowship (201906300026) for her PhD studies at the Erasmus Medical Center, Rotterdam, the Netherlands. EM is supported by Netherlands Organisation for Scientific Research (ZonMW Off Road grant). TSB is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. Funding bodies did not have any influence on study design, results, and data interpretation or final manuscript.

Funding Information:
-phs000755.v2.p1: “BrainSpan Atlas of the Human Brain”. The datasets used for the analysis described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000406.v2.p1. Submission of the data, phs000406.v2.p1, to dbGaP was provided by Dr. Nenad Sestan. Collection of the data and analysis was supported by grants from the National Institutes of Health (MH089929, MH081896, and MH090047). Additional support was provided by the Kavli Foundation, a James S. McDonnell Foundation Scholar Award, NARSAD, and the Foster-Davis Foundation.

Funding Information:
-phs000791.v1.p1: “Roadmap Epigenomics Program - UCSF”. Funding support for the NIH Roadmap Epigenomics Program was provided through the NIH Common Fund (Office of Strategic Coordination). Support for collection of datasets and samples was provided by a series of UO1 cooperative agreements with The Broad Institute [1U01ES017155-01], The Ludwig Institute for Cancer Research [1U01ES017166-01], The University of California San Francisco [1U01ES017154-01], and The University of Washington [1U01ES017156-01]. Data analysis and coordination were supported by an agreement with Baylor College of Medicine [1U01DA025956-01]. Assistance with data curation was supplied by GEO, and data access and visualization was supported by the NCBI.

Funding Information:
-phs001438.v1.p1: “The dynamic landscape of open chromatin during human cortical neurogenesis”. Datasets from this study used for the analyses described in this manuscript were generated in the Geschwind laboratory and supported by NIH grants to D.H.G. (5R01MH060233; 5R01MH100027; 3U01MH103339; 1R01MH110927; 1R01MH094714). Datasets were obtained from dbGaP found at http://www.ncbi.nlm.nih.gov/gap through dbGaP study accession numbers phs001438.v1.p1.

Publisher Copyright:
© 2021, The Author(s).

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