DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell.
Ontology highlight
ABSTRACT:
SUBMITTER: Li X
PROVIDER: S-EPMC8314462 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Topologically associating domains (TADs) are functional chromatin units with hierarchical structure. However, the existence, prevalence, and dynamics of such hierarchy in single cells remain unexplored. Here, a new generation TAD-like domain (TLD) detection algorithm, named deDoc2, to decode the hierarchy of TLDs in single cells, is reported. With dynamic programming, deDoc2 seeks genome partitions with global minimal structure entropy for both whole and local contact matrix. Notably, deDoc2 outperforms state-of-the-art tools and is one of only two tools able to identify the hierarchy of TLDs in single cells. By applying deDoc2, it is showed that the hierarchy of TLDs in single cells is highly dynamic during cell cycle, as well as among human brain cortex cells, and that it is associated with cellular identity and functions. Thus, the results demonstrate the abundance of information potentially encoded by TLD hierarchy for functional regulation. The deDoc2 can be freely accessed at https://github.com/zengguangjie/deDoc2.
| S-EPMC10369259 | biostudies-literature
Project description:Post-translational histone modifications modulate chromatin activity to affect gene expression. How chromatin states underlie lineage choice in single cells is relatively unexplored. We develop sort-assisted single-cell chromatin immunocleavage (sortChIC) and map active (H3K4me1 and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in the mouse bone marrow. During differentiation, hematopoietic stem and progenitor cells (HSPCs) acquire active chromatin states mediated by cell-type-specifying transcription factors, which are unique for each lineage. By contrast, most alterations in repressive marks during differentiation occur independent of the final cell type. Chromatin trajectory analysis shows that lineage choice at the chromatin level occurs at the progenitor stage. Joint profiling of H3K4me1 and H3K9me3 demonstrates that cell types within the myeloid lineage have distinct active chromatin but share similar myeloid-specific heterochromatin states. This implies a hierarchical regulation of chromatin during hematopoiesis: heterochromatin dynamics distinguish differentiation trajectories and lineages, while euchromatin dynamics reflect cell types within lineages.
| S-EPMC9925381 | biostudies-literature
Project description:Nuclear compartmentalization of active and inactive chromatin is thought to occur through microphase separation mediated by interactions between loci of similar type. The nature and dynamics of these interactions are not known. We developed liquid chromatin Hi-C to map the stability of associations between loci. Before fixation and Hi-C, chromosomes are fragmented, which removes strong polymeric constraint, enabling detection of intrinsic locus-locus interaction stabilities. Compartmentalization is stable when fragments are larger than 10-25 kb. Fragmentation of chromatin into pieces smaller than 6 kb leads to gradual loss of genome organization. Lamin-associated domains are most stable, whereas interactions for speckle- and polycomb-associated loci are more dynamic. Cohesin-mediated loops dissolve after fragmentation. Liquid chromatin Hi-C provides a genome-wide view of chromosome interaction dynamics.
| S-EPMC7946813 | biostudies-literature
Project description:MotivationTopologically associating domains (TADs) are fundamental building blocks of 3D genome. TAD-like domains in single cells are regarded as the underlying genesis of TADs discovered in bulk cells. Understanding the organization of TAD-like domains helps to get deeper insights into their regulatory functions. Unfortunately, it remains a challenge to identify TAD-like domains on single-cell Hi-C data due to its ultra-sparsity.ResultsWe propose scKTLD, an in silico tool for the identification of TAD-like domains on single-cell Hi-C data. It takes Hi-C contact matrix as the adjacency matrix for a graph, embeds the graph structures into a low-dimensional space with the help of sparse matrix factorization followed by spectral propagation, and the TAD-like domains can be identified using a kernel-based changepoint detection in the embedding space. The results tell that our scKTLD is superior to the other methods on the sparse contact matrices, including downsampled bulk Hi-C data as well as simulated and experimental single-cell Hi-C data. Besides, we demonstrated the conservation of TAD-like domain boundaries at single-cell level apart from heterogeneity within and across cell types, and found that the boundaries with higher frequency across single cells are more enriched for architectural proteins and chromatin marks, and they preferentially occur at TAD boundaries in bulk cells, especially at those with higher hierarchical levels.Availability and implementationscKTLD is freely available at https://github.com/lhqxinghun/scKTLD.
| S-EPMC10960928 | biostudies-literature
Project description:Sequential Oligopaints DNA FISH is an imaging technique that measures higher-order genome folding at single-allele resolution via multiplexed, probe-based tracing. Currently there is a paucity of algorithms to identify 3D genome features in sequential Oligopaints data. Here, we present FISHnet, a graph theory method based on optimization of network modularity to detect chromatin domains and boundaries in pairwise distance matrices. FISHnet uncovers cell type-specific domain-like folding patterns on single alleles, thus enabling future studies aiming to elucidate the role for single-cell folding variation on genome function.
| S-EPMC11212945 | biostudies-literature
Project description:Topologically associated domains (TADs) are crucial chromatin structural units. Evidence has illustrated that RNA-chromatin and RNA-RNA spatial interactions, so-called RNA-associated interactions (RAIs), may be associated with TAD-like domains (TLDs). To decode hierarchical TLDs from RAIs, we proposed SuperTLD, a domain detection algorithm incorporating imputation. We applied SuperTLD on four RAI data sets and compared TLDs with the TADs identified from the corresponding Hi-C datasets. The TLDs and TADs share a moderate similarity of hierarchies ≥ 0.5312 and the finest structures ≥ 0.8295. Comparison between boundaries and domains further demonstrated the novelty of TLDs. Enrichment analysis of epigenetic characteristics illustrated that the novel TLDs exhibit an enriched CTCF by 0.6245 fold change and H3 histone marks enriched within domains. GO analysis on the TLD novel boundaries exhibited enriched diverse terms, revealing TLDs' formation mechanism related closely to gene regulation.
| S-EPMC9410901 | biostudies-literature
Project description:BackgroundMechanisms underlying genome 3D organization and domain formation in the mammalian nucleus are not completely understood. Multiple processes such as transcriptional compartmentalization, DNA loop extrusion and interactions with the nuclear lamina dynamically act on chromatin at multiple levels. Here, we explore long-range interaction patterns between topologically associated domains (TADs) in several cell types.ResultsWe find that TAD long-range interactions are connected to many key features of chromatin organization, including open and closed compartments, compaction and loop extrusion processes. Domains that form large TAD cliques tend to be repressive across cell types, when comparing gene expression, LINE/SINE repeat content and chromatin subcompartments. Further, TADs in large cliques are larger in genomic size, less dense and depleted of convergent CTCF motifs, in contrast to smaller and denser TADs formed by a loop extrusion process.ConclusionsOur results shed light on the organizational principles that govern repressive and active domains in the human genome.
| S-EPMC8254932 | biostudies-literature
Project description:Gene expression programs change over time, differentiation and development, and in response to stimuli. However, nearly all techniques for profiling gene expression in single cells do not directly capture transcriptional dynamics. In the present study, we present a method for combined single-cell combinatorial indexing and messenger RNA labeling (sci-fate), which uses combinatorial cell indexing and 4-thiouridine labeling of newly synthesized mRNA to concurrently profile the whole and newly synthesized transcriptome in each of many single cells. We used sci-fate to study the cortisol response in >6,000 single cultured cells. From these data, we quantified the dynamics of the cell cycle and glucocorticoid receptor activation, and explored their intersection. Finally, we developed software to infer and analyze cell-state transitions. We anticipate that sci-fate will be broadly applicable to quantitatively characterize transcriptional dynamics in diverse systems.
| S-EPMC7416490 | biostudies-literature
Project description:Large topologically associated domains (TADs) contain irregularly spaced nucleosome clutches, and interactions between such clutches are thought to aid the compaction of these domains. Here, we reconstituted TAD-sized chromatin fibers containing hundreds of nucleosomes on native source human and lambda-phage DNA and compared their mechanical properties at the single-molecule level with shorter '601' arrays with various nucleosome repeat lengths. Fluorescent imaging showed increased compaction upon saturation of the DNA with histones and increasing magnesium concentration. Nucleosome clusters and their structural fluctuations were visualized in confined nanochannels. Force spectroscopy revealed not only similar mechanical properties of the TAD-sized fibers as shorter fibers but also large rupture events, consistent with breaking the interactions between distant clutches of nucleosomes. Though the arrays of native human DNA, lambda-phage and '601' DNA featured minor differences in reconstitution yield and nucleosome stability, the fibers' global structural and mechanical properties were similar, including the interactions between nucleosome clutches. These single-molecule experiments quantify the mechanical forces that stabilize large TAD-sized chromatin domains consisting of disordered, dynamically interacting nucleosome clutches and their effect on the condensation of large chromatin domains.
| S-EPMC9481575 | biostudies-literature
Project description:Delineating gene regulatory networks that orchestrate cell-type specification is a continuing challenge for developmental biologists. Single-cell analyses offer opportunities to address these challenges and accelerate discovery of rare cell lineage relationships and mechanisms underlying hierarchical lineage decisions. Here, we describe the molecular analysis of mouse pancreatic endocrine cell differentiation using single-cell transcriptomics, chromatin accessibility assays coupled to genetic labeling, and cytometry-based cell purification. We uncover transcription factor networks that delineate β-, α-, and δ-cell lineages. Through genomic footprint analysis, we identify transcription factor-regulatory DNA interactions governing pancreatic cell development at unprecedented resolution. Our analysis suggests that the transcription factor Neurog3 may act as a pioneer transcription factor to specify the pancreatic endocrine lineage. These findings could improve protocols to generate replacement endocrine cells from renewable sources, like stem cells, for diabetes therapy.
| S-EPMC9245718 | biostudies-literature