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

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Soheil Yousefi ◽  
Ruizhi Deng ◽  
Kristina Lanko ◽  
Eva Medico Salsench ◽  
Anita Nikoncuk ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Human Brain ◽  
Brain Development ◽  
Fetal Brain ◽  
Regulatory Elements ◽  
Developmental Genetics ◽  
Brain Disorders ◽  
Genetic Changes ◽  
Human Brain Development ◽  
Depth Analysis

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.

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

2021 ◽  
Author(s):  
Soheil Yousefi ◽  
Ruizhi Deng ◽  
Kristina Lanko ◽  
Eva Medico Salsench ◽  
Anita Nikoncuk ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Human Brain ◽  
Brain Development ◽  
Fetal Brain ◽  
Regulatory Elements ◽  
Developmental Genetics ◽  
Brain Disorders ◽  
Genetic Changes ◽  
Human Brain Development ◽  
Depth Analysis

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 complex and can be affected by 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 unrecognised 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. Results: Here we performed an integrative computational analysis of virtually all currently available epigenome data sets related to human fetal brain. 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, these regions 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: Our compendium of high-confidence enhancers will assist in deciphering the mechanism behind developmental genetics of the human brain and will be relevant to uncover missing heritability in human genetic brain disorders.

scholarly journals Sex differences in gene expression in the human fetal brain

2018 ◽  
Author(s):  
Heath E. O’Brien ◽  
Eilis Hannon ◽  
Aaron R. Jeffries ◽  
William Davies ◽  
Matthew J. Hill ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Human Brain ◽  
Brain Development ◽  
Developmental Disorders ◽  
Fetal Brain ◽  
Human Fetal Brain ◽  
Human Brain Development ◽  
Early Human ◽  
Sex Biases

ABSTRACTWidespread structural, chemical and molecular differences have been reported between the male and female human brain. Although several neurodevelopmental disorders are more commonly diagnosed in males, little is known regarding sex differences in early human brain development. Here, we used RNA sequencing data from a large collection of human brain samples from the second trimester of gestation (N = 120) to assess sex biases in gene expression within the human fetal brain. In addition to 43 genes (102 Ensembl transcripts) transcribed from the Y-chromosome in males, we detected sex differences in the expression of 2558 autosomal genes (2723 Ensembl transcripts) and 155 genes on the X-chromosome (207 Ensembl transcripts) at a false discovery rate (FDR) < 0.1. Genes exhibiting sex-biased expression in human fetal brain are enriched for high-confidence risk genes for autism and other developmental disorders. Male-biased genes are enriched for expression in neural progenitor cells, whereas female-biased genes are enriched for expression in Cajal-Retzius cells and glia. All gene- and transcript-level data are provided as an online resource (available at http://fgen.psycm.cf.ac.uk/FBSeq1) through which researchers can search, download and visualize data pertaining to sex biases in gene expression during early human brain development.

scholarly journals §Using organoids to study human brain development and evolution

2021 ◽  
Author(s):  
Wai‐Kit Chan ◽  
Rana Fetit ◽  
Rosie Griffiths ◽  
Helen Marshall ◽  
John O Mason ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Human Brain Development ◽  
Development And Evolution

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

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