Engineering 3D genome organization

Wang, Haifeng; Han, Meihua; Qi, Lei S.

doi:10.1038/s41576-020-00325-5

Cited by 43 publications

(36 citation statements)

References 187 publications

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“…The combination, in this ample disease modeling cohort, of endophenotypes that are highly specific at the functional level and actionable at the molecular level, lays the foundation for rational drug screening studies. Finally, considering the KS1 enhancer dysregulation in light of the increasing relevance of long-range enhancer-promoter interactions 10 , future studies should focus on unveiling the impact of KMT2D loss-of-function on 3D genome organization, also in the context of the emerging potential of genome organization engineering for the treatment of human diseases 60 .…”

Section: Discussionmentioning

confidence: 99%

KMT2D haploinsufficiency in Kabuki syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

Gabriele

Vitriolo

Cuvertino

et al. 2021

Preprint

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Kabuki syndrome (KS) is a rare multisystem disorder, characterized by intellectual disability, growth delay, and distinctive craniofacial features. It is mostly caused by de novo mutations of KMT2D, which is responsible for histone H3lysine 4 mono-methylation (H3K4me1) that marks active and poised enhancers. We assessed the impact of KMT2D mutations on chromatin and transcriptional regulation in a cohort of multiple KS1 tissues, including primary patient samples and disease-relevant lineages, namely cortical neurons (iN), neural crest stem cells (NCSC), and mesenchymal cells (MC). In parallel, we generated an isogenic line derived from human embryonic stem cells (hESC) for the stepwise characterization of neural precursors and mature neurons. We found that transcriptional dysregulation was particularly pronounced in cortical neurons and widely affected synapse activity pathways. This was consistent with highly specific alterations of spontaneous network-bursts patterns evidenced by Micro-electrode-array (MEA)-based neural network. Profiling of H3K4me1 unveiled the almost complete uncoupling between this chromatin mark and the effects on transcription, which is instead reflected by defects in H3K27ac. Finally, we identified the direct targets of KMT2D in mature cortical neurons, uncovering TEAD2 as the main mediator of KMT2D haploinsufficiency. Our results uncover the multi-tissue architecture of KS1 dysregulation and define a unique electrical phenotype and its molecular underpinnings for the cortical neuronal lineage.

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Section: Discussionmentioning

confidence: 99%

KMT2D haploinsufficiency in Kabuki syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

Gabriele

Vitriolo

Cuvertino

et al. 2021

Preprint

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“…Clarifying the mechanisms that lead to the observed diversity may help to understand the functional roles of TADs in different organisms and the relationship between genome function and 3D genome organization, such as whether high-order chromatin structures contribute to genome function or just a result of genome function. Additionally, understanding of principles of 3D genome folding, formation mechanisms, and sequence determinants of key chromatin features in plants would also facilitate sequence-based modeling and engineering of genome 3D architecture 85,86 . Increasing Hi-C data from different plants and advancing genome capture technology will facilitate more and better comparative analyses.…”

Section: Discussionmentioning

confidence: 99%

The 3D architecture of the pepper (Capsicum annum) genome and its relationship to function and evolution

Liao

Wang

Zhu

et al. 2021

Preprint

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The architecture of topologically associating domains (TADs) varies across plant genomes. Understanding the functional consequences of this diversity requires insights into the pattern, structure, and function of TADs. Here, we present a comprehensive investigation of the 3D genome organization of pepper (Capsicum annuum) and its association with gene expression and genomic variants. We report the first chromosome-scale long-read genome assembly of pepper and generate Hi-C contact maps for four tissues. The contact maps indicate that 3D structure varies somewhat across tissues, but generally the genome was segregated into subcompartments that were correlated with transcriptional state. In addition, chromosomes were almost continuously spanned by TADs, with the most prominent found in large genomic regions that were rich in retrotransposons. A substantial fraction of TAD boundaries were demarcated by chromatin loops, suggesting loop extrusion is a major mechanism for TAD formation; many of these loops were bordered by genes, especially in highly repetitive regions, resulting in gene clustering in three dimensional space. Integrated analysis of Hi-C profiles and transcriptomes showed that change in 3D chromatin structures (e.g. subcompartments, TADs, and loops) was not the primary mechanism contributing to differential gene expression between tissues, but chromatin structure does play a role in transcription stability. TAD boundaries were significantly enriched for breaks of synteny and depletion of sequence variation, suggesting that TADs constrain patterns of genome structural evolution in plants. Together, our work provides insights into principles of 3D genome folding in large plant genomes and its association with function and evolution.

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“…For further information on CRISPR in 3D genomics we refer readers to Zhang & Li (2020) and Wang et␣al . (2021). In addition to investigating the 3D genome, Hi‐C can also be used to investigate chromatin state following chromosomal fusions (Mudd et␣al .…”

Section: Hi‐c‐sequencing and Related Methods For Investigating The 3d...mentioning

confidence: 99%

Opportunity to improve livestock traits using 3D genomics

et al. 2021

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The advent of high-throughput chromosome conformation capture and sequencing (Hi-C) has enabled researchers to probe the 3D architecture of the mammalian genome in a genome-wide manner. Simultaneously, advances in epigenomic assays, such as chromatin immunoprecipitation and sequencing (ChIP-seq) and DNase-seq, have enabled researchers to study cis-regulatory interactions and chromatin accessibility across the same genomewide scale. The use of these data has revealed many unique insights into gene regulation and disease pathomechanisms in several model organisms. With the advent of these highthroughput sequencing technologies, there has been an ever-increasing number of datasets available for study; however, this is often limited to model organisms. Livestock species play critical roles in the economies of developing and developed nations alike. Despite this, they are greatly underrepresented in the 3D genomics space; Hi-C and related technologies have the potential to revolutionise livestock breeding by enabling a more comprehensive understanding of how production traits are controlled. The growth in human and model organism Hi-C data has seen a surge in the availability of computational tools for use in 3D genomics, with some tools using machine learning techniques to predict features and improve dataset quality. In this review, we provide an overview of the 3D genome and discuss the status of 3D genomics in livestock before delving into advancing the field by drawing inspiration from research in human and mouse. We end by offering future directions for livestock research in the field of 3D genomics.

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Engineering 3D genome organization

Cited by 43 publications

References 187 publications

KMT2D haploinsufficiency in Kabuki syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

KMT2D haploinsufficiency in Kabuki syndrome disrupts neuronal function through transcriptional and chromatin rewiring independent of H3K4-monomethylation

The 3D architecture of the pepper (Capsicum annum) genome and its relationship to function and evolution

Opportunity to improve livestock traits using 3D genomics

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