3DeFDR: statistical methods for identifying cell type-specific looping interactions in 5C and Hi-C data

Fernandez, Lindsey R.; Gilgenast, Thomas G.; Phillips-Cremins, Jennifer E.

doi:10.1186/s13059-020-02061-9

Cited by 16 publications

(11 citation statements)

References 72 publications

(120 reference statements)

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“…To quantify the link between TAD/subTAD boundaries and IZ genomic placement, we identified a total of 23,851 chromatin domains genome-wide in Hi-C data for human ES cells using our graph-theory-based method 3DNetMod 20 ( Supplementary Methods and Supplementary Table 1 ). We also applied statistical methods developed by our laboratory and others to identify dot-like structures representative of bona fide looping interactions 8 , 21 , 22 . We identified 16,922 dots genome wide in ensemble Hi-C maps of human ES cells.…”

Section: Mainmentioning

confidence: 99%

Cohesin-mediated loop anchors confine the locations of human replication origins

Emerson

Zhao

Cook

et al. 2022

Nature

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DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3–6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.

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Section: Mainmentioning

confidence: 99%

Cohesin-mediated loop anchors confine the locations of human replication origins

Emerson

Zhao

Cook

et al. 2022

Nature

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“…5C Interaction Analysis. 5C analysis steps were performed as described (Gilgenast et al, 2019;Fernandez et al, 2020). Briefly, paired-end reads were aligned to the 5C primer pseudo-genome using Bowtie, allowing only reads with one unique alignment to pass filtering.…”

Section: Rnaseq Analysismentioning

confidence: 99%

Reliance of neuronal gene expression on cohesin scales with chromatin loop length

Calderón

Weiss

Beagan

et al. 2021

Preprint

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Cohesin and CTCF are major drivers of 3D genome organization. Even though human mutations underscore the importance of cohesin and CTCF for neurodevelopment, their role in neurons is only just beginning to be addressed. Here we conditionally ablate Rad21 in cortical neurons, revealing a prominent role for cohesin in the expression of genes that facilitate neuronal maturation, homeostasis, and activation. In agreement with recent reports, activity-dependent genes were downregulated at baseline. However, in contrast to current models that attribute impaired activity-dependent gene expression to a role for cohesin and CTCF in anchoring enhancer-promoter contacts, we show that nearly all activity-dependent genes remain inducible in the absence of cohesin. While CTCF-based chromatin loops were substantially weakened, long-range contacts still formed robustly between activity-dependent enhancers and their target immediate early gene promoters. We suggest a model where neuronal cohesin facilitates the precise level of activity-dependent gene expression, rather than inducibility per se, and where inducibility of activity-dependent gene expression is linked to cohesin-independent enhancer-promoter contacts. These data expand our understanding of the importance of cohesin-independent enhancer-promoter contacts in regulating gene expression.

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“…Compartment A, enriched for transcriptionally active genes, and compartment B, enriched for transcriptionally inactive genes and gene deserts, correspond closely with the iLADs and LADs, respectively, identified by DamID (van Steensel and Belmont 2017). Hi-C topological maps have been further partitioned into sub-compartments, Topological Associated Domains (TADs), and looped-domains, with and without CTCF-anchors (Nora et al 2012; Dixon et al 2012; Rao et al 2014; Fernandez et al 2020).…”

Section: Resultsmentioning

confidence: 99%

Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries

Gholamalamdari

Zhang

Chen

et al. 2021

Preprint

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Large-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.

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3DeFDR: statistical methods for identifying cell type-specific looping interactions in 5C and Hi-C data

Cited by 16 publications

References 72 publications

Cohesin-mediated loop anchors confine the locations of human replication origins

Cohesin-mediated loop anchors confine the locations of human replication origins

Reliance of neuronal gene expression on cohesin scales with chromatin loop length

Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries

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