Global meta‐analysis of over 50 years of multidisciplinary and international collaborations on transmissible cancers

International audienceAlthough transmissible cancers have, so far, only been documented in three independent animal groups, they not only impact animals that have high economic, environmental and social significance, but they are also one of the most virulent parasitic life forms. Currently known transmissible cancers traverse terrestrial and marine environments, and are predicted to be more widely distributed across animal groups; thus, the implementation of effective collaborative scientific networks is important for combating existing and emerging forms. Here, we quantify how collaborative effort on the three known transmissible cancers has advanced through the formation of collaborative networks among institutions and disciplines. These three cancers occur in bivalves (invertebrates—disseminated neoplasia; DN), Tasmanian devils (vertebrate—marsupial; devil facial tumour disease; DFTD) and dogs (vertebrate—eutherian mammal; canine transmissible venereal tumour; CTVT). Research on CTVT and DN has been conducted since 1876 and 1969, respectively, whereas systematic research on DFTD only started in 2006. Yet, collaborative effort on all three diseases is global, encompassing six major Scopus subject areas. Collaborations steadily increased between 1963 and 2006 for CTVT and DN, with similar acceleration for all three cancers since 2006. Network analyses demonstrated that scientists are organizing themselves into efficient collaborative networks; however, these networks appear to be far stronger for DFTD and DN, possibly due to the recent detection of new strains adding impetus to research and associated publications (enhancing citation trajectories). In particular, global and multidisciplinary collaborations formed almost immediately after DFTD research was initiated, leading to similar research effort and relatively greater research outputs compared to the other two diseases. Therefore, in the event of outbreaks of new lineages of existing transmissible cancers, or the discovery of new transmissible cancers in the future, the rapid formation of international collaborations spanning relevant disciplines is vital for the efficient management of these diseases

Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells

DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo

Base-Pair Resolution DNA Methylation Sequencing Reveals Profoundly Divergent Epigenetic Landscapes in Acute Myeloid Leukemia

We have developed an enhanced form of reduced representation bisulfite sequencing with extended genomic coverage, which resulted in greater capture of DNA methylation information of regions lying outside of traditional CpG islands. Applying this method to primary human bone marrow specimens from patients with Acute Myelogeneous Leukemia (AML), we demonstrated that genetically distinct AML subtypes display diametrically opposed DNA methylation patterns. As compared to normal controls, we observed widespread hypermethylation in IDH mutant AMLs, preferentially targeting promoter regions and CpG islands neighboring the transcription start sites of genes. In contrast, AMLs harboring translocations affecting the MLL gene displayed extensive loss of methylation of an almost mutually exclusive set of CpGs, which instead affected introns and distal intergenic CpG islands and shores. When analyzed in conjunction with gene expression profiles, it became apparent that these specific patterns of DNA methylation result in differing roles in gene expression regulation. However, despite this subtype-specific DNA methylation patterning, a much smaller set of CpG sites are consistently affected in both AML subtypes. Most CpG sites in this common core of aberrantly methylated CpGs were hypermethylated in both AML subtypes. Therefore, aberrant DNA methylation patterns in AML do not occur in a stereotypical manner but rather are highly specific and associated with specific driving genetic lesions

Prospects for incorporation of epigenetic biomarkers in human health and environmental risk assessment of chemicals

Epigenetic mechanisms have gained relevance in human health and environmental studies, due to their pivotal role in disease, gene x environment interactions and adaptation to environmental change and/or contamination. Epigenetic mechanisms are highly responsive to external stimuli and a wide range of chemicals has been shown to determine specific epigenetic patterns in several organisms. Furthermore, the mitotic/meiotic inheritance of such epigenetic marks as well as the resulting changes in gene expression and cell/organismal phenotypes has now been demonstrated. Therefore, epigenetic signatures are interesting candidates for linking environmental exposures to disease as well as informing on past exposures to stressors. Accordingly, epigenetic biomarkers could be useful tools in both prospective and retrospective risk assessment but epigenetic endpoints are currently not yet incorporated into risk assessments. Achieving a better understanding on this apparent impasse, as well as identifying routes to promote the application of epigenetic biomarkers within environmental risk assessment frameworks are the objectives of this review. We first compile evidence from human health studies supporting the use of epigenetic exposure-associated changes as reliable biomarkers of exposure. Then, specifically focusing on environmental science, we examine the potential and challenges of developing epigenetic biomarkers for environmental fields, and discuss useful organisms and appropriate sequencing techniques to foster their development in this context. Finally, we discuss the practical incorporation of epigenetic biomarkers in the environmental risk assessment of chemicals, highlighting critical data gaps and making key recommendations for future research within a regulatory context

Patient‐Specific Organoid and Organ‐on‐a‐Chip: 3D Cell‐Culture Meets 3D Printing and Numerical Simulation

The last few decades have witnessed diversified in vitro models to recapitulate the architecture and function of living organs or tissues and contribute immensely to advances in life science. Two novel 3D cell culture models: 1) Organoid, promoted mainly by the developments of stem cell biology and 2) Organ‐on‐a‐chip, enhanced primarily due to microfluidic technology, have emerged as two promising approaches to advance the understanding of basic biological principles and clinical treatments. This review describes the comparable distinct differences between these two models and provides more insights into their complementarity and integration to recognize their merits and limitations for applicable fields. The convergence of the two approaches to produce multi‐organoid‐on‐a‐chip or human organoid‐on‐a‐chip is emerging as a new approach for building 3D models with higher physiological relevance. Furthermore, rapid advancements in 3D printing and numerical simulations, which facilitate the design, manufacture, and results‐translation of 3D cell culture models, can also serve as novel tools to promote the development and propagation of organoid and organ‐on‐a‐chip systems. Current technological challenges and limitations, as well as expert recommendations and future solutions to address the promising combinations by incorporating organoids, organ‐on‐a‐chip, 3D printing, and numerical simulation, are also summarized.Organ and organoid‐on‐chips are synergistic engineering approaches to faithfully reconstitute in vitro organ‐level structures and functions with high structural fidelity, cellular consistency, environmental control ability, integration as well as through‐put. This review also details current achievements, barriers, and future prospective of these promising combinations by incorporating organoid, organ‐on‐a‐chip, 3D printing, and numerical simulation toward patient‐specific disease‐on‐a‐chip and human‐on‐a‐chip.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168371/1/adbi202000024_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168371/2/adbi202000024.pd

Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA

Abstract Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH

DNA methylation and gene expression relationships display subtype-specific differences.

<p>CpG islands and shores across the genome were categorized into those located upstream from a transcription start site (TSS), overlapping a TSS or located downstream from a TSS. Boxplots are plotted that illustrate the maximum DNA methylation levels at CpGs within these CpG islands and CpG shores for the top 15th percentile expressed genes (right) and the bottom 15th percentile expressed genes (left). Each row shows a representative sample for each type: Normal bone marrow (top); IDH-mut AML (middle) and MLLr AML (bottom). In all sample types CpG islands overlapping a TSS displayed lower methylation levels in highly expressed genes and higher methylation levels in genes that were expressed at low levels. In MLLr AMLs this relationship between expression and methylation levels further extended into CpG shores, and was also observed at CpG islands and shores upstream and downstream from the TSS. IDH-mut AMLs, and to a lesser degree NBM samples, displayed higher methylation levels at CpG shores of genes with high expression levels, while low methylation levels were observed at these shores for genes expressed at low levels.</p

Aberrant methylation targets a minimally overlapping set of CpGs in IDH-mut and MLLr AMLs.

<p>(A) Venn diagram representing differentially methylated CpGs identified for IDH-mut and MLLr AMLs from amongst the 574,178 CpGs adequately represented (>10× coverage) across all six samples. Most DMCs are unique to either AML subtype, with minimal amount of events occurring at common sites across IDH-mut and MLLr. (B) Horizontal barplot comparing the methylation status of CpG sites at DMCs in IDH-mut AML (top) and MLLr AML (bottom). Magenta depicts >25% hypermethylation relative to NBM, green represents >25% hypomethylation and gray represents no differential methylation. Most DMCs are non-overlapping between the two subtypes of AML and display opposite changes in methylation. However, amongst the smaller set of DMCs that do overlap between the two AML subtypes, the vast majority (76.6%) are concordantly changed, with a clear predominance for aberrrant hypermethylation of those sites (79%).</p

Overlap of differentially methylated cytosines with CTCF, MLL and HOXA9 binding sites, and enhancer regions.

<p>Overlap of differentially methylated cytosines with CTCF, MLL and HOXA9 binding sites, and enhancer regions.</p