MIA-Sig: multiplex chromatin interaction analysis by signal processing and statistical algorithms.
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PROVIDER: S-EPMC6876102 | BioStudies |
REPOSITORIES: biostudies
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Project description:The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus1. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)2, and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)3, have revealed topologically associating domains4 with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription5-7. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C8 potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis9 but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription.
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Project description:Recent advances in ligation-free, genome-wide chromatin interaction mapping such as SPRITE and ChIA-Drop have enabled the identification of simultaneous interactions involving multiple genomic loci within the same nuclei, which are informative to delineate higher-order genome organization and gene regulation mechanisms at single-nucleus resolution. Unfortunately, computational methods for analyzing multi-way chromatin interaction data are significantly underexplored. Here we develop an algorithm, called MATCHA, based on hypergraph representation learning where multi-way chromatin interactions are represented as hyperedges. Applications to SPRITE and ChIA-Drop data suggest that MATCHA is effective to denoise the data and make <i>de novo</i> predictions, which greatly enhances the data quality for analyzing the properties of multi-way chromatin interactions. MATCHA provides a promising framework to significantly improve the analysis of multi-way chromatin interaction data and has the potential to offer unique insights into higher-order chromosome organization and function. MATCHA is freely available for download here: https://github.com/ma-compbio/MATCHA.
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Project description:Emerging 3D genome mapping efforts suggest complex chromosomal folding structures. However, the true multiplex nature of chromatin interactions has yet to be fully explored. Here, we describe a chromatin interaction analysis by droplet-based sequencing (ChIA-Drop). In ChIA-Drop, individual chromatin complexes are partitioned into droplets that contain a gel bead of DNA-barcoded primers, such that tethered chromatin DNA fragments are uniquely indexed and amplified for sequencing and mapping to demarcate multiplex chromatin contacts. Thus, ChIA-Drop can identify complex chromatin interactions with unprecedented single-molecule precision, which is not possible using methods that analyze pairwise contacts via proximity ligation. We demonstrate that multiplex chromatin interactions predominantly contribute to topologically associated domains with high heterogeneity, and that multivalent promoter-centered interactions provide a topological model for gene transcription. Overall design: The microfluidics device (10X Genomics’ Chromium instrument) produces Gel beads in Emulsion (GEM) with chromatin complexes for complex-specific DNA barcoding and amplification. Barcoded DNA amplicons from all GEMs (droplets) are pooled for DNA sequencing and mapping for identifying chromatin interactions.
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Project description:The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.
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Project description:Familial adenomatous polyposis (FAP) is an autosomal-dominantly inherited form of colorectal cancer (CRC) caused by mutation in the adenomatous polyposis coli (APC) gene. Our ability to exhaustively screen for APC mutations identify microsatellite-stable and APC-mutation negative familial CRC patients, enabling us to search for novel genes. We performed genome-wide scan on two affected siblings of one family and 88 ethnicity- and gender-matched healthy controls to identify deletions shared by the siblings. Combined loss of heterozygosity, copy number and allelic-specific copy number analysis uncovered 5 shared deletions. Long-range polymerase chain reaction (PCR) confirmed chromosome 19q13 deletion, which was subsequently found in one other family. The 32 kb deleted region harbors the CYP2A7 gene and was enriched with enhancer, repressor and insulator sites. The wildtype allele was lost in the polyps of the proband. Further, real-time RT-PCR assays showed that expressions of MIA and MIA-RAB4B located 35 kb upstream of the deletion, were up-regulated in the polyps compared to the matched mucosa of the proband. MIA-RAB4B, the read-through long non-coding RNA (lncRNA), RAB4B, PIM2 and TAOK1 share common binding site of a microRNA, miR-24, in their 3'UTRs. PIM2 and TAOK1, two target oncogenes of miR-24, were co-ordinately up-regulated with MIA-RAB4B in the polyps, suggesting that MIA-RAB4B could function as competitive endogenous RNA to titrate miR-24 away from its other targets. The data suggest that the 19.13 deletion disrupted chromatin boundary, leading to altered expression of several genes and lncRNA, could contribute to colorectal cancer via novel genetic and epigenetic mechanisms.
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Project description:RNAi targeting a conserved C. elegans cyclophilin, sig-7, causes defective development and embryonic arrest consistent with a global defect in transcription. The goal of this study was to compare the transcript levels in sig-7(RNAi) embryos to those of L4440/RNAi control embryos to examine the global transcriptional effect caused by of loss of sig-7 function Examination of RNA levels using RNAseq in 2 replicate samples each of early embryos from sig-7(RNAi) and RNAi controls
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Project description:ChIA-PET is a high-throughput mapping technology that reveals long-range chromatin interactions and provides insights into the basic principles of spatial genome organization and gene regulation mediated by specific protein factors. Recently, we showed that a single ChIA-PET experiment provides information at all genomic scales of interest, from the high-resolution locations of binding sites and enriched chromatin interactions mediated by specific protein factors, to the low resolution of nonenriched interactions that reflect topological neighborhoods of higher-order chromosome folding. This multilevel nature of ChIA-PET data offers an opportunity to use multiscale 3D models to study structural-functional relationships at multiple length scales, but doing so requires a structural modeling platform. Here, we report the development of 3D-GNOME (3-Dimensional Genome Modeling Engine), a complete computational pipeline for 3D simulation using ChIA-PET data. 3D-GNOME consists of three integrated components: a graph-distance-based heat map normalization tool, a 3D modeling platform, and an interactive 3D visualization tool. Using ChIA-PET and Hi-C data derived from human B-lymphocytes, we demonstrate the effectiveness of 3D-GNOME in building 3D genome models at multiple levels, including the entire genome, individual chromosomes, and specific segments at megabase (Mb) and kilobase (kb) resolutions of single average and ensemble structures. Further incorporation of CTCF-motif orientation and high-resolution looping patterns in 3D simulation provided additional reliability of potential biologically plausible topological structures.
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Project description:Genomic data are becoming increasingly valuable as we develop methods to utilize the information at scale and gain a greater understanding of how genetic information relates to biological function. Advances in synthetic biology and the decreased cost of sequencing are increasing the amount of privately held genomic data. As the quantity and value of private genomic data grows, so does the incentive to acquire and protect such data, which creates a need to store and process these data securely. We present an algorithm for the Secure Interrogation of Genomic DataBases (SIG-DB). The SIG-DB algorithm enables databases of genomic sequences to be searched with an encrypted query sequence without revealing the query sequence to the Database Owner or any of the database sequences to the Querier. SIG-DB is the first application of its kind to take advantage of locality-sensitive hashing and homomorphic encryption to allow generalized sequence-to-sequence comparisons of genomic data.
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Project description:RNAi targeting a conserved C. elegans cyclophilin, sig-7, causes defective development and embryonic arrest consistent with a global defect in transcription. The goal of this study was to compare the location of RNA Pol II in sig-7(RNAi) embryos to the localization in L4440/RNAi control embryos to examine the global effect of loss of sig-7 on RNA Pol II regulation and its distribution within gene bodies anti-AMA-1 ChIP in 2 replicates each of sig-7(RNAi) and RNAi control early stage embryos
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Project description:Melanoma inhibitory activity/cartilage-derived retinoic acid-sensitive protein (MIA/CD-RAP) is a small soluble protein secreted from chondrocytes. It was identified as the prototype of a family of extracellular proteins adopting an SH3 domain-like fold. In order to study the consequences of MIA/CD-RAP deficiency in detail we used mice with a targeted gene disruption of MIA/CD-RAP (MIA-/-) and analyzed cartilage organisation and differentiation in in vivo and in vitro models. Cartilage formation and regeneration was determined in models for osteoarthritis and fracture healing in vivo, in addition to in vitro studies using mesenchymal stem cells of MIA-/- mice. Interestingly, our data suggest enhanced chondrocytic regeneration in the MIA-/- mice, modulated by enhanced proliferation and delayed differentiation. Expression analysis of cartilage tissue derived from MIA-/- mice revealed strong downregulation of nuclear RNA-binding protein 54-kDa (p54(nrb)), a recently described modulator of Sox9 activity. In this study, we present p54(nrb) as a mediator of MIA/CD-RAP to promote chondrogenesis. Taken together, our data indicate that MIA/CD-RAP is required for differentiation in cartilage potentially by regulating signaling processes during differentiation.
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