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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Yousefi, Soheil, Deng, Ruizhi, Lanko, Kristina, Salsench, Eva Medico, Nikoncuk, Anita, van der Linde, Herma C., Perenthaler, Elena, van Ham, Tjakko J., Mulugeta, Eskeatnaf, Barakat, Tahsin Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Research
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524963/
https://www.ncbi.nlm.nih.gov/pubmed/34663447
http://dx.doi.org/10.1186/s13073-021-00980-1
_version_ 1784585580736151552
author Yousefi, Soheil
Deng, Ruizhi
Lanko, Kristina
Salsench, Eva Medico
Nikoncuk, Anita
van der Linde, Herma C.
Perenthaler, Elena
van Ham, Tjakko J.
Mulugeta, Eskeatnaf
Barakat, Tahsin Stefan
author_facet Yousefi, Soheil
Deng, Ruizhi
Lanko, Kristina
Salsench, Eva Medico
Nikoncuk, Anita
van der Linde, Herma C.
Perenthaler, Elena
van Ham, Tjakko J.
Mulugeta, Eskeatnaf
Barakat, Tahsin Stefan
author_sort Yousefi, Soheil
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00980-1.
format Online
Article
Text
id pubmed-8524963
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-85249632021-10-22 Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance Yousefi, Soheil Deng, Ruizhi Lanko, Kristina Salsench, Eva Medico Nikoncuk, Anita van der Linde, Herma C. Perenthaler, Elena van Ham, Tjakko J. Mulugeta, Eskeatnaf Barakat, Tahsin Stefan Genome Med Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-021-00980-1. BioMed Central 2021-10-19 /pmc/articles/PMC8524963/ /pubmed/34663447 http://dx.doi.org/10.1186/s13073-021-00980-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Yousefi, Soheil
Deng, Ruizhi
Lanko, Kristina
Salsench, Eva Medico
Nikoncuk, Anita
van der Linde, Herma C.
Perenthaler, Elena
van Ham, Tjakko J.
Mulugeta, Eskeatnaf
Barakat, Tahsin Stefan
Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title_full Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title_fullStr Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title_full_unstemmed Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title_short Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
title_sort comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524963/
https://www.ncbi.nlm.nih.gov/pubmed/34663447
http://dx.doi.org/10.1186/s13073-021-00980-1
work_keys_str_mv AT yousefisoheil comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT dengruizhi comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT lankokristina comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT salsenchevamedico comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT nikoncukanita comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT vanderlindehermac comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT perenthalerelena comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT vanhamtjakkoj comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT mulugetaeskeatnaf comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance
AT barakattahsinstefan comprehensivemultiomicsintegrationidentifiesdifferentiallyactiveenhancersduringhumanbraindevelopmentwithclinicalrelevance

Ejemplares similares