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Folding Principles of Human Brain Genome
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Folding Principles of Human Brain Genome

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (1 March 2022) | Viewed by 14912

Special Issue Editors

Dr. Hyejung Won

E-Mail Website
Guest Editor
Department of Genetics and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Interests: 3D genomics; GWAS; non-coding variants; psychiatric genetics
Dr. Douglas Phanstiel

E-Mail Website
Guest Editor
Department of Genetics and Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Interests: 3D chromatin structure; gene regulation; data visualization; Alzheimer’s Disease

Special Issue Information

Dear Colleagues,

The three-dimensional structure of the human genome is an important regulatory unit for transcriptional control. The precise control of genome organization is essential for brain development and function, which is tightly coupled with complex spatiotemporal transcriptional programs. A deeper understanding of the mechanisms of the 3D chromatin structure, coupled with detailed maps of 3D chromatin contacts in a region- and cell-type-specific fashion will provide critical insights into the control of brain development, function, and disease. An emerging body of evidence has shown that genetic variants associated with brain disorders are often located in the non-coding DNA and their function needs to be addressed within the spatial organization of the genome. For example, some variants communicate with genes that are located thousands of base pairs away, emphasizing the need to study their function within gene regulatory networks. Some variants alter chromatin topology and have profound effects on transcriptional programs.

In this Special Issue of “Folding Principles of Human Brain Genome,” we aim to bring together experts in 3D genome organization, gene regulation, and neuroscience to discuss recent advances in techniques to profile 3D genome in a cell-type-specific and high-resolution manner and discuss how these advances contribute to our understanding of brain biology. Collectively, this issue will provide a platform to demonstrate how 3D genome organization can revolutionize our understanding of gene regulatory mechanisms of brain development, function, and disease.

Dr. Hyejung Won
Dr. Douglas Phanstiel
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • 3D chromatin structure 
  • Epigenetics 
  • Gene regulation 
  • Brain disorders 
  • Brain development 
  • Brain function

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Published Papers (4 papers)

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Research

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15 pages, 9231 KiB  
Article
InsuLock: A Weakly Supervised Learning Approach for Accurate Insulator Prediction, and Variant Impact Quantification
by Shushrruth Sai Srinivasan, Yanwen Gong, Siwei Xu, Ahyeon Hwang, Min Xu, Matthew J. Girgenti and Jing Zhang
Genes 2022, 13(4), 621; https://doi.org/10.3390/genes13040621 - 30 Mar 2022
Cited by 1 | Viewed by 2987
Abstract
Mapping chromatin insulator loops is crucial to investigating genome evolution, elucidating critical biological functions, and ultimately quantifying variant impact in diseases. However, chromatin conformation profiling assays are usually expensive, time-consuming, and may report fuzzy insulator annotations with low resolution. Therefore, we propose a [...] Read more.
Mapping chromatin insulator loops is crucial to investigating genome evolution, elucidating critical biological functions, and ultimately quantifying variant impact in diseases. However, chromatin conformation profiling assays are usually expensive, time-consuming, and may report fuzzy insulator annotations with low resolution. Therefore, we propose a weakly supervised deep learning method, InsuLock, to address these challenges. Specifically, InsuLock first utilizes a Siamese neural network to predict the existence of insulators within a given region (up to 2000 bp). Then, it uses an object detection module for precise insulator boundary localization via gradient-weighted class activation mapping (~40 bp resolution). Finally, it quantifies variant impacts by comparing the insulator score differences between the wild-type and mutant alleles. We applied InsuLock on various bulk and single-cell datasets for performance testing and benchmarking. We showed that it outperformed existing methods with an AUROC of ~0.96 and condensed insulator annotations to ~2.5% of their original size while still demonstrating higher conservation scores and better motif enrichments. Finally, we utilized InsuLock to make cell-type-specific variant impacts from brain scATAC-seq data and identified a schizophrenia GWAS variant disrupting an insulator loop proximal to a known risk gene, indicating a possible new mechanism of action for the disease. Full article
(This article belongs to the Special Issue Folding Principles of Human Brain Genome)
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Review

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12 pages, 1066 KiB  
Review
3D Genome Plasticity in Normal and Diseased Neurodevelopment
by Amara Plaza-Jennings, Aditi Valada and Schahram Akbarian
Genes 2022, 13(11), 1999; https://doi.org/10.3390/genes13111999 - 1 Nov 2022
Cited by 4 | Viewed by 2337
Abstract
Non-random spatial organization of the chromosomal material inside the nuclei of brain cells emerges as an important regulatory layer of genome organization and function in health and disease. Here, we discuss how integrative approaches assessing chromatin in context of the 3D genome is [...] Read more.
Non-random spatial organization of the chromosomal material inside the nuclei of brain cells emerges as an important regulatory layer of genome organization and function in health and disease. Here, we discuss how integrative approaches assessing chromatin in context of the 3D genome is providing new insights into normal and diseased neurodevelopment. Studies in primate (incl. human) and rodent brain have confirmed that chromosomal organization in neurons and glia undergoes highly dynamic changes during pre- and early postnatal development, with potential for plasticity across a much wider age window. For example, neuronal 3D genomes from juvenile and adult cerebral cortex and hippocampus undergo chromosomal conformation changes at hundreds of loci in the context of learning and environmental enrichment, viral infection, and neuroinflammation. Furthermore, locus-specific structural DNA variations, such as micro-deletions, duplications, repeat expansions, and retroelement insertions carry the potential to disrupt the broader epigenomic and transcriptional landscape far beyond the boundaries of the site-specific variation, highlighting the critical importance of long-range intra- and inter-chromosomal contacts for neuronal and glial function. Full article
(This article belongs to the Special Issue Folding Principles of Human Brain Genome)
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19 pages, 1901 KiB  
Review
Understanding Regulatory Mechanisms of Brain Function and Disease through 3D Genome Organization
by Weifang Liu, Wujuan Zhong, Jiawen Chen, Bo Huang, Ming Hu and Yun Li
Genes 2022, 13(4), 586; https://doi.org/10.3390/genes13040586 - 25 Mar 2022
Cited by 8 | Viewed by 4368
Abstract
The human genome has a complex and dynamic three-dimensional (3D) organization, which plays a critical role for gene regulation and genome function. The importance of 3D genome organization in brain development and function has been well characterized in a region- and cell-type-specific fashion. [...] Read more.
The human genome has a complex and dynamic three-dimensional (3D) organization, which plays a critical role for gene regulation and genome function. The importance of 3D genome organization in brain development and function has been well characterized in a region- and cell-type-specific fashion. Recent technological advances in chromosome conformation capture (3C)-based techniques, imaging approaches, and ligation-free methods, along with computational methods to analyze the data generated, have revealed 3D genome features at different scales in the brain that contribute to our understanding of genetic mechanisms underlying neuropsychiatric diseases and other brain-related traits. In this review, we discuss how these advances aid in the genetic dissection of brain-related traits. Full article
(This article belongs to the Special Issue Folding Principles of Human Brain Genome)
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16 pages, 1861 KiB  
Review
Implications of Dosage Deficiencies in CTCF and Cohesin on Genome Organization, Gene Expression, and Human Neurodevelopment
by Christopher T. Cummings and M. Jordan Rowley
Genes 2022, 13(4), 583; https://doi.org/10.3390/genes13040583 - 25 Mar 2022
Cited by 9 | Viewed by 4456
Abstract
Properly organizing DNA within the nucleus is critical to ensure normal downstream nuclear functions. CTCF and cohesin act as major architectural proteins, working in concert to generate thousands of high-intensity chromatin loops. Due to their central role in loop formation, a massive research [...] Read more.
Properly organizing DNA within the nucleus is critical to ensure normal downstream nuclear functions. CTCF and cohesin act as major architectural proteins, working in concert to generate thousands of high-intensity chromatin loops. Due to their central role in loop formation, a massive research effort has been dedicated to investigating the mechanism by which CTCF and cohesin create these loops. Recent results lead to questioning the direct impact of CTCF loops on gene expression. Additionally, results of controlled depletion experiments in cell lines has indicated that genome architecture may be somewhat resistant to incomplete deficiencies in CTCF or cohesin. However, heterozygous human genetic deficiencies in CTCF and cohesin have illustrated the importance of their dosage in genome architecture, cellular processes, animal behavior, and disease phenotypes. Thus, the importance of considering CTCF or cohesin levels is especially made clear by these heterozygous germline variants that characterize genetic syndromes, which are increasingly recognized in clinical practice. Defined primarily by developmental delay and intellectual disability, the phenotypes of CTCF and cohesin deficiency illustrate the importance of architectural proteins particularly in neurodevelopment. We discuss the distinct roles of CTCF and cohesin in forming chromatin loops, highlight the major role that dosage of each protein plays in the amplitude of observed effects on gene expression, and contrast these results to heterozygous mutation phenotypes in murine models and clinical patients. Insights highlighted by this comparison have implications for future research into these newly emerging genetic syndromes. Full article
(This article belongs to the Special Issue Folding Principles of Human Brain Genome)
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