Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines

Jacobson, Elsie C.; Grand, Ralph S.; Perry, Jo K.; Vickers, Mark H.; Olins, Ada L.; O’Sullivan, Justin M.

doi:10.1016/j.ygeno.2019.05.009

Cited by 18 publications

(14 citation statements)

References 64 publications

(140 reference statements)

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“…Therefore, it is possible that the Hi-C interactions and eQTL sets were not representative of the tissues in which they were tested. It is also possible that karyotype issues within the immortalized cell lines have introduced non-physiological interactions into the analysis (34). However, in spite of this obvious technical bias, our results were reproducible and tissuespecific (FDR < 0.05) and this provide an overall systems-level understanding of the regulatory interactions observed between AiD-associated SNPs and their target genes.…”

Section: Discussionmentioning

confidence: 72%

Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach

et al. 2021

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Autoimmune diseases (AiDs) are complex heterogeneous diseases characterized by hyperactive immune responses against self. Genome-wide association studies have identified thousands of single nucleotide polymorphisms (SNPs) associated with several AiDs. While these studies have identified a handful of pleiotropic loci that confer risk to multiple AiDs, they lack the power to detect shared genetic factors residing outside of these loci. Here, we integrated chromatin contact, expression quantitative trait loci and protein-protein interaction (PPI) data to identify genes that are regulated by both pleiotropic and non-pleiotropic SNPs. The PPI analysis revealed complex interactions between the shared and disease-specific genes. Furthermore, pathway enrichment analysis demonstrated that the shared genes co-occur with disease-specific genes within the same biological pathways. In conclusion, our results are consistent with the hypothesis that genetic risk loci associated with multiple AiDs converge on a core set of biological processes that potentially contribute to the emergence of polyautoimmunity.

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Section: Discussionmentioning

confidence: 72%

Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach

et al. 2021

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“…According to the undetectable level of p-STAT3 in all groups, the regulatory effect of JAK/STAT pathway in this process requires further investigation. Notably, HL-60 as a cancer cell line has several new mutations over time and exhibits genetic/epigenetic heterogeneity in cells provided from different sources 54 . Furthermore, the mRNA expression of STAT3 did not show any significant changes in response to fenbendazole treatment, however, total STAT3 proteins after fenbendazole treatment is significantly higher.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional drug repositioning and cheminformatics approach for differentiation therapy of leukaemia cells

KalantarMotamedi

Ejeian

Sabouhi

et al. 2021

Sci Rep

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Differentiation therapy is attracting increasing interest in cancer as it can be more specific than conventional chemotherapy approaches, and it has offered new treatment options for some cancer types, such as treating acute promyelocytic leukaemia (APL) by retinoic acid. However, there is a pressing need to identify additional molecules which act in this way, both in leukaemia and other cancer types. In this work, we hence developed a novel transcriptional drug repositioning approach, based on both bioinformatics and cheminformatics components, that enables selecting such compounds in a more informed manner. We have validated the approach for leukaemia cells, and retrospectively retinoic acid was successfully identified using our method. Prospectively, the anti-parasitic compound fenbendazole was tested in leukaemia cells, and we were able to show that it can induce the differentiation of leukaemia cells to granulocytes in low concentrations of 0.1 μM and within as short a time period as 3 days. This work hence provides a systematic and validated approach for identifying small molecules for differentiation therapy in cancer.

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“…Table S1-2). Hi-C maps can be leveraged to provide information on SVs (Harewood et al 2017;Dixon et al 2018;Jacobson et al 2019) since physical proximity mediated by SVs are reflected in novel contacts in the Hi-C (Harewood et al 2017;Dixon et al 2018;Jacobson et al 2019) map (Figure 1). We used Hi-C analysis to identify 306 SVs, the majority of which were also identified by mate-pair sequencing (Figure S2b-d).…”

Section: Resultsmentioning

confidence: 99%

Somatic structural variant formation is guided by and influences genome architecture

Sidiropoulos

Mardin

Rodríguez-González

et al. 2021

Preprint

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The occurrence and formation of genomic structural variants (SV) is known to be influenced by the 3D chromatin architecture , but the extent and magnitude has been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the massive complex rearrangements, which allowed us to study the sources of SV formation and their consequences on gene regulation. We observe an action-reaction interplay whereby the 3D chromatin architecture directly impacts on the location and formation of SVs. In turn, the SVs reshape the chromatin organization to alter the local topologies, replication timing and gene regulation in cis. We show that genomic compartments and replication timing are important determinants for juxtaposing distant loci to form SVs across 30 different cancer types with a pronounced abundance of SVs between early replicating regions in uterine cancer. We find that SVs frequently occur at 3D loop-anchors, cause compartment switching and changes in replication timing, and that this is a major source of SV-mediated effects on nearby gene expression changes.

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Hi-C detects novel structural variants in HL-60 and HL-60/S4 cell lines

Cited by 18 publications

References 64 publications

Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach

Unravelling the Shared Genetic Mechanisms Underlying 18 Autoimmune Diseases Using a Systems Approach

Transcriptional drug repositioning and cheminformatics approach for differentiation therapy of leukaemia cells

Somatic structural variant formation is guided by and influences genome architecture

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