Osteosarcoma is the most common primary tumor of bone. Osteosarcomas are rare in humans, but occur more commonly in dogs. A comparative approach to studying osteosarcoma has highlighted many clinical and biologic aspects of the disease that are similar between dogs and humans; however, important species-specific differences are becoming increasingly recognized. In this review, we describe risk factors for the development of osteosarcoma in dogs and humans, including height and body size, genetics, and conditions that increase turnover of bone-forming cells, underscoring the concept that stochastic mutational events associated with cellular replication are likely to be the major molecular drivers of this disease. We also discuss adaptive, cancer-protective traits that have evolved in large, long-lived mammals, and how increasing size and longevity in the absence of natural selection can account for the elevated bone cancer risk in modern domestic dogs.

Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F_{(1, 19)} = 7.492, p = 0.013] whereby responders had an increase in methylation and non-responders had a decrease in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F_{(1, 19)} = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Increases in FKBP5 methylation after treatment in responders as compared to decreases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.

Eye movement deviations, particularly deficits of initial sensorimotor processing and sustained pursuit maintenance, and antisaccade inhibition errors, are established intermediate phenotypes for psychotic disorders. We here studied eye movement measures of 849 participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study (schizophreniaN=230, schizoaffective disorderN=155, psychotic bipolar disorderN=206 and healthy controlsN=258) as quantitative phenotypes in relation to genetic data, while controlling for genetically derived ancestry measures, age and sex. A mixed-modeling genome-wide association studies approach was used including ~4.4 million genotypes (PsychChip and 1000 Genomes imputation). Across participants, sensorimotor processing at pursuit initiation was significantly associated with a single nucleotide polymorphism inIPO8(12p11.21,P=8 × 10⁻¹¹), whereas suggestive associations with sustained pursuit maintenance were identified with SNPs inSH3GL2(9p22.2,P=3 × 10⁻⁸). In participants of predominantly African ancestry, sensorimotor processing was also significantly associated with SNPs inPCDH12(5q31.3,P=1.6 × 10⁻¹⁰), and suggestive associations were observed withNRSN1(6p22.3,P=5.4 × 10⁻⁸) andLMO7(13q22.2,P=7.3x10⁻⁸), whereas antisaccade error rate was significantly associated with a non-coding region at chromosome 7 (P=6.5 × 10⁻⁹). Exploratory pathway analyses revealed associations with nervous system development and function for 40 top genes with sensorimotor processing and pursuit maintenance (P=4.9 × 10⁻²–9.8 × 10⁻⁴). Our findings suggest novel patterns of genetic variation relevant for brain systems subserving eye movement control known to be impaired in psychotic disorders. They include genes involved in nuclear trafficking and gene silencing (IPO8), fast axonal guidance and synaptic specificity (PCDH12), transduction of nerve signals (NRSN1), retinal degeneration (LMO7), synaptic glutamate release (SH3GL2), and broader nervous system development and function.

The transcriptional mechanisms driving lineage specification during development are still largely unknown, as the interplay of multiple transcription factors makes it difficult to dissect these molecular events. Using a cell-based differentiation platform to probe transcription function, we investigated the role of the key paraxial mesoderm and skeletal myogenic commitment factors—mesogenin 1 (Msgn1), T-box 6 (Tbx6), forkhead box C1 (Foxc1), paired box 3 (Pax3), Paraxis, mesenchyme homeobox 1 (Meox1), sine oculis-related homeobox 1 (Six1), and myogenic factor 5 (Myf5)—in paraxial mesoderm and skeletal myogenesis. From this study, we define a genetic hierarchy, with Pax3 emerging as the gatekeeper between the presomitic mesoderm and the myogenic lineage. By assaying chromatin accessibility, genomic binding and transcription profiling in mesodermal cells from mouse and human Pax3-induced embryonic stem cells and Pax3-null embryonic day (E)9.5 mouse embryos, we identified conserved Pax3 functions in the activation of the skeletal myogenic lineage through modulation of Hedgehog, Notch, and bone morphogenetic protein (BMP) signaling pathways. In addition, we demonstrate that Pax3 molecular function involves chromatin remodeling of its bound elements through an increase in chromatin accessibility and cooperation with sine oculis-related homeobox 4 (Six4) and TEA domain family member 2 (Tead2) factors. To our knowledge, these data provide the first integrated analysis of Pax3 function, demonstrating its ability to remodel chromatin in mesodermal cells from developing embryos and proving a mechanistic footing for the transcriptional hierarchy driving myogenesis. Lineage specification during embryonic development relies on the activation of specific transcriptional programs required for defining cellular functions within each tissue. Transcription factors (TFs) play a critical part in gene activation/repression by promoting the formation of regulatory hubs at the elements associated with their target genes. Through hierarchical expression of TFs, cells within the developing embryo gradually shape their genomic landscape and ultimately restrict their differentiation potential. Here, we dissect the complex network of TFs involved in the specification of mesoderm toward the skeletal myogenic lineage by generating embryonic stem cell lines in which TF expression is controlled by a doxycycline-dependent on–off system. Using a combination of cell differentiation and genomic assays, we defined the TF hierarchy “Msgn1→Pax3→Myf5,” in which paired box 3 (Pax3) emerges as the key determinant for the specification of the myogenic fate. We show that Pax3 occupies several sites proximal to myogenic genes and that binding to these elements is associated with increase in chromatin accessibility, a hallmark of active regulatory elements. Although the ability of Pax3 to modulate chromatin accessibility is comparable between myogenic and nonmyogenic cells, Pax3 genomic binding and motif preferences are cell-dependent. In addition, we identify that cooperation with sine oculis-related homeobox 4 (Six4) and TEA domain family member 2 (Tead2) is instrumental for the robust Pax3-mediated myogenic commitment, thus indicating that combination of TFs and chromatin remodeling are both required for lineage commitment.

Significance: Cancer immunotherapies, such as immune checkpoint blockade, work by stimulating immune cells to kill tumors. Unfortunately, not all patients respond to checkpoint treatment, which also causes autoimmune side effects due to self-reactive immune cell activation. This study uncovers immune subtypes that respond best to this immunotherapy and reveals methods to reinvigorate dysfunctional antitumor immune responses. We show that self-reactive CD8 T cells can be pathogenic or nonresponsive to checkpoint blockade therapy depending on their activation status. In addition, tolerant self-reactive CD8 T cells bear striking similarity to dysfunctional tumor-specific CD8 T cells. Finally, we demonstrate that previously tolerant self-specific CD8 T cells can eliminate aggressive tumors bearing self-antigens without concomitant autoimmunity after robust antigenic vaccination in concert with PD-L1 blockade.

Specification of the mesodermal lineages requires a complex set of morphogenetic events orchestrated by interconnected signaling pathways and gene regulatory networks. The transcription factor Sox7 has critical functions in differentiation of multiple mesodermal lineages, including cardiac, endothelial, and hematopoietic. Using a doxycycline-inducible mouse embryonic stem cell line, we have previously shown that expression of Sox7 in cardiovascular progenitor cells promotes expansion of endothelial progenitor cells (EPCs). In this study, we show that the ability of Sox7 to promote endothelial cell fate occurs at the expense of the cardiac lineage. Using ChIP-Seq coupled with ATAC-Seq we identify downstream target genes of Sox7 in cardiovascular progenitor cells and by integrating these data with transcriptomic analyses, we define Sox7 -dependent gene programs specific to cardiac and EPCs. Furthermore, we demonstrate a protein–protein interaction between SOX7 and GATA4 and provide evidence that SOX7 interferes with the transcriptional activity of GATA4 on cardiac genes. In addition, we show that Sox7 modulates WNT and BMP signaling during cardiovascular differentiation. Our data represent the first genome-wide analysis of Sox7 function and reveal a critical role for Sox7 in regulating signaling pathways that affect cardiovascular progenitor cell differentiation.