DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary ...tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context ('solo-WCGWs') identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.
Recent discoveries suggest cysteine-stabilized toxins and antimicrobial peptides have structure-activity parallels derived by common ancestry. Here, human antimicrobial peptide hBD-2 and rattlesnake ...venom-toxin crotamine were compared in phylogeny, 3D structure, target celi specificity, and mechanisms of action. Results indicate a striking degree of structural and phylogenetic congruence. Importantly, these polypeptides also exhibited functional reciprocity: (i) they exerted highly similar antimicrobial pH optima and spectra; (ii) both altered membrane potential consistent with ion channel-perturbing activities; and (iii) both peptides induced phosphatidylserine accessibility in eukaryotic cells. However, the $Na_v $ channel-inhibitor tetrodotoxin antagonized hBD-2 mechanisms, but not those of crotamine. As crotamine targets eukaryotic ion Channels, computational docking was used to compare hBD-2 versus crotamine interactions with prototypic bacterial, fungal, or mammalian $K_v $ Channels. Models support direct interactions of each peptide with $K_v $ Channels. However, while crotamine localized to occlude $K_v $ Channels in eukaryotic but not prokaryotic cells, hBD-2 interacted with prokaryotic and eukaryotic $K_v $ Channels but did not occlude either. Together, these results support the hypothesis that antimicrobial and cytotoxic polypeptides have ancestral structurefunction homology, but evolved to preferentially target respective microbial versus mammalian ion Channels via residue-specific interactions. These insights may accelerate development of antiinfective or therapeutic peptides that selectively target microbial or abnormal host cells.
In this communication we introduce an efficient implementation of adaptive biasing that greatly improves the speed of free energy computation in molecular dynamics simulations. We investigated the ...use of accelerated simulations to inform on compound design using a recently reported and clinically relevant inhibitor of the chromatin regulator BRD4 (bromodomain-containing protein 4). Benchmarking on our local compute cluster, our implementation achieves up to 2.5 times more force calls per day than plumed2. Results of five 1 μs-long simulations are presented, which reveal a conformational switch in the BRD4 inhibitor between a binding competent and incompetent state. Stabilization of the switch led to a -3 kcal/mol improvement of absolute binding free energy. These studies suggest an unexplored ligand design principle and offer new actionable hypotheses for medicinal chemistry efforts against this druggable epigenetic target class.
Extensive changes in DNA methylation are common in cancer and may contribute to oncogenesis through transcriptional silencing of tumor-suppressor genes. Genome-scale studies have yielded important ...insights into these changes but have focused on CpG islands or gene promoters. We used whole-genome bisulfite sequencing (bisulfite-seq) to comprehensively profile a primary human colorectal tumor and adjacent normal colon tissue at single-basepair resolution. Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines. We confirmed the confluence of hypermethylation and hypomethylation within these domains in 25 diverse colorectal tumors and matched adjacent tissue. We propose that widespread DNA methylation changes in cancer are linked to silencing programs orchestrated by the three-dimensional organization of chromatin within the nucleus.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed Partially Methylated Domains (PMDs). We profiled 39 diverse ...primary tumors and 8 matched adjacent tissues using Whole-Genome Bisulfite Sequencing (WGBS), and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (“Solo-WCGWs”) revealed previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increases with age in both fetal and postnatal tissues, appearing to track accumulation of cell divisions beginning early in life. In cancer, the degree of PMD hypomethylation correlates with somatic mutation density and expression of cell-cycle dependent genes, reinforcing its mitotic clock-like role. We propose that late replication leads to progressive methylation loss throughout an individual's lifespan, potentially contributing to the onset of cancer and acting as a biomarker for cellular aging.
Citation Format: Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen, Peter W. Laird, Benjamin P. Berman. DNA methylation loss in late-replicating domains is linked to mitotic cell division abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5327.
Genome annotation is critical to understand the function of disease variants, especially for clinical applications. To meet this need there are segmentations available from public consortia ...reflecting varying unsupervised approaches to functional annotation based on epigenetics data, but there remains a need for transparent, reproducible, and easily interpreted genomic maps of the functional biology of chromatin. We introduce a new methodological framework for defining a combinatorial epigenomic model of chromatin state on a web database,
StateHub
. In addition, we created an annotation tool for bioconductor,
StatePaintR
, which accesses these models and uses them to rapidly (on the order of seconds) produce chromatin state segmentations in standard genome browser formats. Annotations are fully documented with change history and versioning, authorship information, and original source files.
StatePaintR
calculates ranks for each state from next-gen sequencing peak statistics, facilitating variant prioritization, enrichment testing, and other types of quantitative analysis.
StateHub
hosts annotation tracks for major public consortia as a resource, and allows users to submit their own alternative models.
Genome annotation is critical to understand the function of disease variants, especially for clinical applications. To meet this need there are segmentations available from public consortia ...reflecting varying unsupervised approaches to functional annotation based on epigenetics data, but there remains a need for transparent, reproducible, and easily interpreted genomic maps of the functional biology of chromatin. We introduce a new methodological framework for defining a combinatorial epigenomic model of chromatin state on a web database,
StateHub. In addition, we created an annotation tool for bioconductor,
StatePaintR, which accesses these models and uses them to rapidly (on the order of seconds) produce chromatin state segmentations in standard genome browser formats. Annotations are fully documented with change history and versioning, authorship information, and original source files.
StatePaintR calculates ranks for each state from next-gen sequencing peak statistics, facilitating variant prioritization, enrichment testing, and other types of quantitative analysis.
StateHub hosts annotation tracks for major public consortia as a resource, and allows users to submit their own alternative models.
In this paper, we describe the design and implementation of a Graphical User Interface (GUI) for Cassandra, a computer application for Virtual Ligand Screening (VLS). The GUI was designed using ...Trolltech QT4 and Perl, and serves the purpose of making the execution of Cassandra more user-friendly. Through this GUI, users can manage multiple concurrent, interactive data paths both on a single machine and on a High Performance Computing Cluster (HPCC). The GUI successfully decreased the complexity and steep learning curve of using Cassandra, and the average time to execute a VLS project. As result, we reduced the time necessary to train new users, increased the number of users, increased the overall efficiency of Cassandra, and optimized data handling and analysis.
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