Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.

Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.

An expanded universe of cancer targets.

The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic characterization does not influence therapy for most patients. Approaches to understand the function and circuitry of cancer genes provide complementary approaches to elucidate both oncogene and non-oncogene dependencies. Emerging work indicates that the diversity of therapeutic targets engendered by non-oncogene dependencies is much larger than the list of recurrently mutated genes. Here we describe a framework for this expanded list of cancer targets, providing novel opportunities for clinical translation.

Molecular Choreography of Acute Exercise.

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

Mfd Dynamically Regulates Transcription via a Release and Catch-Up Mechanism.

The bacterial Mfd ATPase is increasingly recognized as a general transcription factor that participates in the resolution of transcription conflicts with other processes/roadblocks. This function stems from Mfd's ability to preferentially act on stalled RNA polymerases (RNAPs). However, the mechanism underlying this preference and the subsequent coordination between Mfd and RNAP have remained elusive. Here, using a novel real-time translocase assay, we unexpectedly discovered that Mfd translocates autonomously on DNA. The speed and processivity of Mfd dictate a "release and catch-up" mechanism to efficiently patrol DNA for frequently stalled RNAPs. Furthermore, we showed that Mfd prevents RNAP backtracking or rescues a severely backtracked RNAP, allowing RNAP to overcome stronger obstacles. However, if an obstacle's resistance is excessive, Mfd dissociates the RNAP, clearing the DNA for other processes. These findings demonstrate a remarkably delicate coordination between Mfd and RNAP, allowing efficient targeting and recycling of Mfd and expedient conflict resolution.

Redefining macrophage and neutrophil biology in the metastatic cascade.

Tumor cells metastasize to distant organs through a complex series of events that are driven by tumor intrinsic and extrinsic factors. In particular, non-malignant stromal cells, including immune cells, modify tumor metastatic behavior. Of these cells, tumor-associated innate immune cells, particularly macrophages and neutrophils, suppress the cytotoxic activity of innate and adaptive killer cells and interact with tumor cells to promote their growth and malignancy. These findings in mouse cancer models suggest that targeting these sub-populations of immune cells holds therapeutic promise in treating metastatic disease. In this review, we describe the origin and role of the macrophages, neutrophils, and their progenitors in the metastatic cascade and suggest strategies that might enhance cancer therapy.

Reduced expression of MYC increases longevity and enhances healthspan.

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

Extreme redox variations in a superdeep diamond from a subducted slab.

The introduction of volatile-rich subducting slabs to the mantle may locally generate large redox gradients, affecting phase stability, element partitioning and volatile speciation1. Here we investigate the redox conditions of the deep mantle recorded in inclusions in a diamond from Kankan, Guinea. Enstatite (former bridgmanite), ferropericlase and a uniquely Mg-rich olivine (Mg# 99.9) inclusion indicate formation in highly variable redox conditions near the 660 km seismic discontinuity. We propose a model involving dehydration, rehydration and dehydration in the underside of a warming slab at the transition zone-lower mantle boundary. Fluid liberated by dehydration in a crumpled slab, driven by heating from the lower mantle, ascends into the cooler interior of the slab, where the H2O is sequestered in new hydrous minerals. Consequent fractionation of the remaining fluid produces extremely reducing conditions, forming Mg-end-member ringwoodite. This fractionating fluid also precipitates the host diamond. With continued heating, ringwoodite in the slab surrounding the diamond forms bridgmanite and ferropericlase, which is trapped as the diamond grows in hydrous fluids produced by dehydration of the warming slab.

Sublithospheric diamond ages and the supercontinent cycle.

Subduction related to the ancient supercontinent cycle is poorly constrained by mantle samples. Sublithospheric diamond crystallization records the release of melts from subducting oceanic lithosphere at 300-700 km depths1,2 and is especially suited to tracking the timing and effects of deep mantle processes on supercontinents. Here we show that four isotope systems (Rb-Sr, Sm-Nd, U-Pb and Re-Os) applied to Fe-sulfide and CaSiO3 inclusions within 13 sublithospheric diamonds from Juína (Brazil) and Kankan (Guinea) give broadly overlapping crystallization ages from around 450 to 650 million years ago. The intracratonic location of the diamond deposits on Gondwana and the ages, initial isotopic ratios, and trace element content of the inclusions indicate formation from a peri-Gondwanan subduction system. Preservation of these Neoproterozoic-Palaeozoic sublithospheric diamonds beneath Gondwana until its Cretaceous breakup, coupled with majorite geobarometry3,4, suggests that they accreted to and were retained in the lithospheric keel for more than 300 Myr during supercontinent migration. We propose that this process of lithosphere growth-with diamonds attached to the supercontinent keel by the diapiric uprise of depleted buoyant material and pieces of slab crust-could have enhanced supercontinent stability.

Origins of cancer: ain't it just mature cells misbehaving?

A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

MicroRNA-142 Is Critical for the Homeostasis and Function of Type 1 Innate Lymphoid Cells.

Natural killer (NK) cells are cytotoxic type 1 innate lymphoid cells (ILCs) that defend against viruses and mediate anti-tumor responses, yet mechanisms controlling their development and function remain incompletely understood. We hypothesized that the abundantly expressed microRNA-142 (miR-142) is a critical regulator of type 1 ILC biology. Interleukin-15 (IL-15) signaling induced miR-142 expression, whereas global and ILC-specific miR-142-deficient mice exhibited a cell-intrinsic loss of NK cells. Death of NK cells resulted from diminished IL-15 receptor signaling within miR-142-deficient mice, likely via reduced suppressor of cytokine signaling-1 (Socs1) regulation by miR-142-5p. ILCs persisting in Mir142-/- mice demonstrated increased expression of the miR-142-3p target αV integrin, which supported their survival. Global miR-142-deficient mice exhibited an expansion of ILC1-like cells concurrent with increased transforming growth factor-ß (TGF-ß) signaling. Further, miR-142-deficient mice had reduced NK-cell-dependent function and increased susceptibility to murine cytomegalovirus (MCMV) infection. Thus, miR-142 critically integrates environmental cues for proper type 1 ILC homeostasis and defense against viral infection.

Mass Spectrometry-Based Proteogenomics: New Therapeutic Opportunities for Precision Medicine.

Proteogenomics refers to the integration of comprehensive genomic, transcriptomic, and proteomic measurements from the same samples with the goal of fully understanding the regulatory processes converting genotypes to phenotypes, often with an emphasis on gaining a deeper understanding of disease processes. Although specific genetic mutations have long been known to drive the development of multiple cancers, gene mutations alone do not always predict prognosis or response to targeted therapy. The benefit of proteogenomics research is that information obtained from proteins and their corresponding pathways provides insight into therapeutic targets that can complement genomic information by providing an additional dimension regarding the underlying mechanisms and pathophysiology of tumors. This review describes the novel insights into tumor biology and drug resistance derived from proteogenomic analysis while highlighting the clinical potential of proteogenomic observations and advances in technique and analysis tools.

A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.

Lysosomal degradation pathways coordinate the clearance of superfluous and damaged cellular components. Compromised lysosomal degradation is a hallmark of many degenerative diseases, including lysosomal storage diseases (LSDs), which are caused by loss-of-function mutations within both alleles of a lysosomal hydrolase, leading to lysosomal substrate accumulation. Gaucher's disease, characterized by <15% of normal glucocerebrosidase function, is the most common LSD and is a prominent risk factor for developing Parkinson's disease. Here, we show that either of two structurally distinct small molecules that modulate PIKfyve activity, identified in a high-throughput cellular lipid droplet clearance screen, can improve glucocerebrosidase function in Gaucher patient-derived fibroblasts through an MiT/TFE transcription factor that promotes lysosomal gene translation. An integrated stress response (ISR) antagonist used in combination with a PIKfyve modulator further improves cellular glucocerebrosidase activity, likely because ISR signaling appears to also be slightly activated by treatment by either small molecule at the higher doses employed. This strategy of combining a PIKfyve modulator with an ISR inhibitor improves mutant lysosomal hydrolase function in cellular models of additional LSD.

Current and upcoming treatment approaches to uncommon subtypes of PTCL (EATL/MEITL, SPTCL, HSTCL).

Rare subtypes of peripheral T-cell lymphoma (PTCL) including enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and hepatosplenic T-cell lymphoma (HSTCL) are underrepresented in most registry and clinical studies. Most of the literature is obtained from small case series, single-institution retrospective studies and subgroup analyses of the largest studies with few recent and ongoing exceptions. While the pathogenesis and biology of these entities have yet to be fully elucidated, global efforts by the scientific community have started to shed some light on the most frequently deregulated pathways. In this review, we highlight the most pertinent clinical and pathologic features of rare subtypes of PTCL including EATL/MEITL, SPTCL and HSTCL. We also summarize the results of recent developments identifying potential targets for novel therapeutic strategies based on molecular studies. Finally, we highlight the underrepresentation of these rare subtypes in most clinical trials, making evidence-based therapeutic decisions extremely challenging.

Unbalanced MYC break-apart FISH patterns indicate the presence of a MYC rearrangement in HGBCL-DH-BCL2.

ABSTRACT: Fluorescence in situ hybridization (FISH) using break-apart probes is recommended for identifying high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH-BCL2). Unbalanced MYC break-apart patterns, in which the red or green signal is lost, are commonly reported as an equivocal result by clinical laboratories. In a cohort of 297 HGBCL-DH-BCL2, 13% of tumors had unbalanced MYC break-apart patterns with loss of red (LR; 2%) or loss of green (LG; 11%) signal. To determine the significance of these patterns, MYC rearrangements were characterized by sequencing in 130 HGBCL-DH-BCL2, including 3 LR and 14 LG tumors. A MYC rearrangement was identified for 71% of tumors with LR or LG patterns, with the majority involving immunoglobulin loci or other recurrent MYC rearrangement partners. The architecture of these rearrangements consistently preserved the rearranged MYC allele, with the MYC gene predicted to be on the derivative chromosome containing the signal that is still present in nearly all cases. MYC protein expression, MYC messenger RNA expression, and the proportion of tumors expressing the dark-zone signature was not significantly different between balanced and unbalanced groups. These results support a recommendation that unbalanced MYC break-apart FISH patterns be reported as positive for MYC rearrangement in the context of diagnosing HGBCL-DH-BCL2.

The Yolk Sac Feeds Pancreatic Tumors.

In this issue of Immunity, Zhu et al. (2017) report that tumor-associated macrophages in a mouse model of pancreatic ductal adenocarcinoma (PDAC) originate from both the yolk sac (YS) and bone marrow. Differential ablation of these populations indicates that only the YS-derived macrophages promote PDAC progression and growth.

Microbial communication superhighways.

Exchange of information is critical for bacterial social behaviors. Now Dubey and Ben-Yehuda (2011) provide evidence for bacterial "nanotube" conduits that allow microbes to directly exchange cytoplasmic factors. Protein and DNA transfer between distantly related species raises the prospect of a new, widely distributed mechanism of bacterial communication.

Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe.

Following the detection of the new coronavirus1 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its spread outside of China, Europe has experienced large epidemics of coronavirus disease 2019 (COVID-19). In response, many European countries have implemented non-pharmaceutical interventions, such as the closure of schools and national lockdowns. Here we study the effect of major interventions across 11 European countries for the period from the start of the COVID-19 epidemics in February 2020 until 4 May 2020, when lockdowns started to be lifted. Our model calculates backwards from observed deaths to estimate transmission that occurred several weeks previously, allowing for the time lag between infection and death. We use partial pooling of information between countries, with both individual and shared effects on the time-varying reproduction number (Rt). Pooling allows for more information to be used, helps to overcome idiosyncrasies in the data and enables more-timely estimates. Our model relies on fixed estimates of some epidemiological parameters (such as the infection fatality rate), does not include importation or subnational variation and assumes that changes in Rt are an immediate response to interventions rather than gradual changes in behaviour. Amidst the ongoing pandemic, we rely on death data that are incomplete, show systematic biases in reporting and are subject to future consolidation. We estimate that-for all of the countries we consider here-current interventions have been sufficient to drive Rt below 1 (probability Rt < 1.0 is greater than 99%) and achieve control of the epidemic. We estimate that across all 11 countries combined, between 12 and 15 million individuals were infected with SARS-CoV-2 up to 4 May 2020, representing between 3.2% and 4.0% of the population. Our results show that major non-pharmaceutical interventions-and lockdowns in particular-have had a large effect on reducing transmission. Continued intervention should be considered to keep transmission of SARS-CoV-2 under control.