Toward an understanding of the relation between gene regulation and 3D genome organization

High coverage sequences of archaic humans enabled the reconstruction of their DNA methylation patterns. This allowed comparing gene regulation between human groups, and linking such regulatory changes to phenotypic differences. In a previous work, a detailed comparison of DNA methylation in modern humans, archaic humans, and chimpanzees revealed 873 modern human-derived differentially methylated regions (DMRs). To understand the regulatory implications of these DMRs, we defined differentially methylated genes (DMGs) as genes that harbor DMRs in their promoter or gene body. While most of the modern human-derived DMRs could be linked to DMGs, many others remained unassigned. Here, we used information on 3D genome organization to link ~70 out of the remaining 288 unassigned DMRs to genes. Combined with the previously identified DMGs, we reinforce the enrichment of these genes with vocal and facial anatomy, and additionally find significant enrichment with the spinal column, chin, hair, and scalp. These results reveal the importance of 3D genomic organization in understanding gene regulation by DNA methylation.

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Resolving the 3D landscape of transcription-linked mammalian chromatin folding

10.1101/638775 ◽

2019 ◽

Cited By ~ 9

Author(s):

Tsung-Han S. Hsieh ◽

Elena Slobodyanyuk ◽

Anders S. Hansen ◽

Claudia Cattoglio ◽

Oliver J. Rando ◽

...

Keyword(s):

Stem Cells ◽

Gene Regulation ◽

Genome Organization ◽

Regulatory Elements ◽

Genome Architecture ◽

Transcriptional Regulatory Elements ◽

3D Genome ◽

Topologically Associating Domains ◽

Transcriptional Regulatory ◽

Chromatin Folding

ABSTRACTChromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into “microTADs” with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. Intriguingly, we detect “two-start” zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation.ONE SENTENCE SUMMARYTranscriptional regulatory elements shape 3D genome architecture of microTADs.

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Understanding gene regulatory mechanisms based on gene classification

10.1101/2021.10.31.466641 ◽

2021 ◽

Author(s):

Hao Tian ◽

Yueying He ◽

Yue Xue ◽

Yi Qin Gao

Keyword(s):

Gene Regulation ◽

Density Distribution ◽

Genome Organization ◽

Housekeeping Genes ◽

Structural Features ◽

Regulatory Mechanisms ◽

3D Genome ◽

Human Genes ◽

Cpg Dinucleotide ◽

Gene Regulatory

The CpG dinucleotide and its methylation play vital roles in gene regulation as well as 3D genome organization. Previous studies have divided genes into several categories based on the CpG intensity around transcription starting sites (TSS) and found that housekeeping genes tend to possess high CpG density while tissue-specific genes are generally characterized by low CpG density. In this study, we investigated how the CpG density distribution of a gene affects its transcription and regulation pattern. Based on the CpG density distribution around TSS, the human genes are clearly divided into different categories. Not only sequence properties, these different clusters exhibited distinctly different structural features, regulatory mechanisms, and correlation patterns between expression level and CpG/TpG density. These results emphasized that the usage of epigenetic marks in gene regulation is partially rooted in the sequence property of genes, such as their CpG density distribution.

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Toward an understanding of the relation between gene regulation and 3D genome organization

10.1101/2020.01.13.903872 ◽

2020 ◽

Author(s):

Hao Tian ◽

Ying Yang ◽

Sirui Liu ◽

Hui Quan ◽

Yi Qin Gao

Keyword(s):

Gene Regulation ◽

Chromatin Structure ◽

Genome Organization ◽

Network Formation ◽

Expression Profiles ◽

Chromosome Conformation ◽

Tissue Specific ◽

3D Genome ◽

Gene Positioning ◽

3D Chromatin Structure

AbstractThe development and usage of chromosome conformation capture technologies have provided great details on 3D genome organization and provide great opportunities to understand how gene regulation is affected by the 3D chromatin structure. Previously, we identified two types of sequence domains, CGI forest and CGI prairie, which tend to segregate spatially, but to different extent in different tissues/cell states. To further quantify the association of domain segregation with gene regulation and differentiation, we analyzed in this study the distribution of genes of different tissue specificities along the linear genome, and found that the distribution patterns are distinctly different in forests and prairies. The tissue-specific genes (TSGs) are significantly enriched in the latter but not in the former and genes of similar expression profiles among different cell types (co-activation/repression) also tend to cluster in specific prairies. We then analyzed the correlation between gene expression and the spatial contact revealed in Hi-C measurement. Tissue-specific forest-prairie contact formation was found to correlate with the regulation of the TSGs, in particular those in the prairie domains, pointing to the important role gene positioning, in the linear DNA sequence as well as in 3D chromatin structure, plays in gene regulatory network formation.

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Protein factors involved in 3D genome organization & transcription regulation

Endocrine Abstracts ◽

10.1530/endoabs.54.is11 ◽

2018 ◽

Author(s):

Yijun Ruan

Keyword(s):

Transcription Regulation ◽

Genome Organization ◽

3D Genome

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HP1 drives de novo 3D genome reorganization in early Drosophila embryos

Nature ◽

10.1038/s41586-021-03460-z ◽

2021 ◽

Author(s):

Fides Zenk ◽

Yinxiu Zhan ◽

Pavel Kos ◽

Eva Löser ◽

Nazerke Atinbayeva ◽

...

Keyword(s):

Genome Organization ◽

Molecular Mechanisms ◽

High Throughput Sequencing ◽

De Novo ◽

Early Embryo ◽

Heterochromatin Protein ◽

Chromosome Conformation ◽

3D Genome ◽

Genome Reorganization

AbstractFundamental features of 3D genome organization are established de novo in the early embryo, including clustering of pericentromeric regions, the folding of chromosome arms and the segregation of chromosomes into active (A-) and inactive (B-) compartments. However, the molecular mechanisms that drive de novo organization remain unknown1,2. Here, by combining chromosome conformation capture (Hi-C), chromatin immunoprecipitation with high-throughput sequencing (ChIP–seq), 3D DNA fluorescence in situ hybridization (3D DNA FISH) and polymer simulations, we show that heterochromatin protein 1a (HP1a) is essential for de novo 3D genome organization during Drosophila early development. The binding of HP1a at pericentromeric heterochromatin is required to establish clustering of pericentromeric regions. Moreover, HP1a binding within chromosome arms is responsible for overall chromosome folding and has an important role in the formation of B-compartment regions. However, depletion of HP1a does not affect the A-compartment, which suggests that a different molecular mechanism segregates active chromosome regions. Our work identifies HP1a as an epigenetic regulator that is involved in establishing the global structure of the genome in the early embryo.

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Erythrocytes 3D genome organization in vertebrates

Scientific Reports ◽

10.1038/s41598-021-83903-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anastasia Ryzhkova ◽

Alena Taskina ◽

Anna Khabarova ◽

Veniamin Fishman ◽

Nariman Battulin

Keyword(s):

Blood Cells ◽

Genome Organization ◽

Large Scale ◽

Chromatin Condensation ◽

Erythroid Differentiation ◽

Interaction Patterns ◽

3D Interaction ◽

Interphase Chromosome ◽

3D Genome ◽

Contact Maps

AbstractGeneration of mature red blood cells, consisting mainly of hemoglobin, is a remarkable example of coordinated action of various signaling networks. Chromatin condensation is an essential step for terminal erythroid differentiation and subsequent nuclear expulsion in mammals. Here, we profiled 3D genome organization in the blood cells from ten species belonging to different vertebrate classes. Our analysis of contact maps revealed a striking absence of such 3D interaction patterns as loops or TADs in blood cells of all analyzed representatives. We also detect large-scale chromatin rearrangements in blood cells from mammals, birds, reptiles and amphibians: their contact maps display strong second diagonal pattern, representing an increased frequency of long-range contacts, unrelated to TADs or compartments. This pattern is completely atypical for interphase chromosome structure. We confirm that these principles of genome organization are conservative in vertebrate erythroid cells.

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