Showing papers by "Rockefeller University published in 2010"
TL;DR: This study developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs and revealed that these factors bind thousands of sites containing defined sequence motifs and have distinct preferences for exonic versus intronic or coding versus untranslated transcript regions.
2,730 citations
TL;DR: This article reviews theoretical and empirical work using the allostatic load model vis-à-vis the effects of chronic stress on physical and mental health and proposes policies for promoting successful aging.
1,944 citations
TL;DR: It is shown that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4, illustrating that HR and NHEJ compete to process DNA breaks that arise during DNA replication.
1,482 citations
TL;DR: A synthetic compound (I-BET) is described that by ‘mimicking’ acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis.
Abstract: Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
1,407 citations
TL;DR: This review focuses specifically on the links between stress‐related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load.
Abstract: The brain is the key organ of stress reactivity, coping, and recovery processes. Within the brain, a distributed neural circuitry determines what is threatening and thus stressful to the individual. Instrumental brain systems of this circuitry include the hippocampus, amygdala, and areas of the prefrontal cortex. Together, these systems regulate physiological and behavioral stress processes, which can be adaptive in the short-term and maladaptive in the long-term. Importantly, such stress processes arise from bidirectional patterns of communication between the brain and the autonomic, cardiovascular, and immune systems via neural and endocrine mechanisms underpinning cognition, experience, and behavior. In one respect, these bidirectional stress mechanisms are protective in that they promote short-term adaptation (allostasis). In another respect, however, these stress mechanisms can lead to a long-term dysregulation of allostasis in that they promote maladaptive wear-and-tear on the body and brain under chronically stressful conditions (allostatic load), compromising stress resiliency and health. This review focuses specifically on the links between stress-related processes embedded within the social environment and embodied within the brain, which is viewed as the central mediator and target of allostasis and allostatic load.
1,388 citations
TL;DR: CD14dim monocytes were weak phagocytes and did not produce ROS or cytokines in response to cell-surface Toll-like receptors, but selectively produced TNF-α, IL-1β, and CCL3 inresponse to viruses and immune complexes containing nucleic acids, via a proinflammatory TLR7-TLR 8-MyD88-MEK pathway.
1,149 citations
TL;DR: It is demonstrated that multiple and distinct factors are responsible for H3.3 localization at specific genomic locations in mammalian cells.
1,115 citations
TL;DR: A high-throughput genomics approach is used to show that isolates of methicillin-resistant Staphylococcus aureus are precisely differentiated into a global geographic structure and suggest that intercontinental transmission has occurred for nearly four decades.
Abstract: Current methods for differentiating isolates of predominant lineages of pathogenic bacteria often do not provide sufficient resolution to define precise relationships. Here, we describe a high-throughput genomics approach that provides a high-resolution view of the epidemiology and microevolution of a dominant strain of methicillin-resistant Staphylococcus aureus (MRSA). This approach reveals the global geographic structure within the lineage, its intercontinental transmission through four decades, and the potential to trace person-to-person transmission within a hospital environment. The ability to interrogate and resolve bacterial populations is applicable to a range of infectious diseases, as well as microbial ecology.
1,103 citations
TL;DR: It is shown that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignantglioma.
Abstract: The inference of transcriptional networks that regulate transitions into physiological or pathological cellular states remains a central challenge in systems biology. A mesenchymal phenotype is the hallmark of tumour aggressiveness in human malignant glioma, but the regulatory programs responsible for implementing the associated molecular signature are largely unknown. Here we show that reverse-engineering and an unbiased interrogation of a glioma-specific regulatory network reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors (C/EBPbeta and STAT3) emerge as synergistic initiators and master regulators of mesenchymal transformation. Ectopic co-expression of C/EBPbeta and STAT3 reprograms neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the two factors in glioma cells leads to collapse of the mesenchymal signature and reduces tumour aggressiveness. In human glioma, expression of C/EBPbeta and STAT3 correlates with mesenchymal differentiation and predicts poor clinical outcome. These results show that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.
1,078 citations
TL;DR: It is found that B cell division is restricted to the DZ, with a net vector of B cell movement from the D Z to the LZ, and T cell help, and not direct competition for antigen, is the limiting factor in GC selection.
1,045 citations
TL;DR: Recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins are summarized, and how misreading, miswriting and mis-erasing of hist one methylation marks can be associated with oncogenesis and progression are summarized.
Abstract: Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future.
Yale University1, Stanford University2, University of Toronto3, Harvard University4, University of California, Santa Cruz5, University of North Carolina at Chapel Hill6, Ontario Institute for Cancer Research7, New York University8, Stony Brook University9, University of Cambridge10, Hoffmann-La Roche11, Lawrence Berkeley National Laboratory12, University of California, San Diego13, Rockefeller University14, University of Washington15, National Institutes of Health16, University of Michigan17, Fred Hutchinson Cancer Research Center18, Max Planck Society19, Memorial Sloan Kettering Cancer Center20, Weizmann Institute of Science21, Max Delbrück Center for Molecular Medicine22, Cold Spring Harbor Laboratory23, Vanderbilt University24, New York University Abu Dhabi25
TL;DR: These studies identified regions of the nematode and fly genomes that show highly occupied targets (or HOT) regions where DNA was bound by more than 15 of the transcription factors analyzed and the expression of related genes were characterized, providing insights into the organization, structure, and function of the two genomes.
Abstract: We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.
TL;DR: An open standard format for multidimensional microscopy image data is described and it is called on the community to use open image data standards and to insist that all imaging platforms support these file formats.
Abstract: Data sharing is important in the biological sciences to prevent duplication of effort, to promote scientific integrity, and to facilitate and disseminate scientific discovery. Sharing requires centralized repositories, and submission to and utility of these resources require common data formats. This is particularly challenging for multidimensional microscopy image data, which are acquired from a variety of platforms with a myriad of proprietary file formats (PFFs). In this paper, we describe an open standard format that we have developed for microscopy image data. We call on the community to use open image data standards and to insist that all imaging platforms support these file formats. This will build the foundation for an open image data repository.
Vardan Khachatryan, Albert M. Sirunyan, Armen Tumasyan, Wolfgang Adam1 +2197 more•Institutions (149)
TL;DR: The pre-print version of the Published Article can be accessed from the link below - Copyright @ 2010 Springer Verlag as discussed by the authors, which can be viewed as a preprint of the published article.
Abstract: This is the pre-print version of the Published Article, which can be accessed from the link below - Copyright @ 2010 Springer Verlag
TL;DR: It is shown that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1, and Polycomb gene silencing may entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H 2A deubiquitinationBy PR-DUB.
Abstract: Polycomb group (PcG) proteins are transcriptional repressors that modify chromatin and regulate important developmental genes. One chromatin-modifying activity associated with Polycomb is an enzyme that ubiquitinates histone H2A. Here, Scheuermann et al. find a Drosophila PcG complex with H2A deubiquitination activity that is important for gene repression in vivo. Polycomb gene silencing may thus involve a dynamic balance between H2A ubiquitination and deubiquitination. Polycomb group (PcG) proteins are transcriptional repressors that modify chromatin and regulate important developmental genes. One PcG-associated, chromatin-modifying activity is an enzyme that ubiquitinates histone H2A of chromatin. Here, a fruitfly PcG complex that is associated with H2A deubiquitination, and thereby with gene repression, is identified. PcG-mediated gene silencing might thus involve a dynamic balance between ubiquitination and deubiquitination of H2A. Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants1,2,3,4,5,6. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive1,7,8. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes1,2,3,4. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1–4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
TL;DR: It is found that the ATRX–Daxx complex is bound to telomeric chromatin, and that both components of this complex are required for H3.3 deposition at telomeres in murine embryonic stem cells (ESCs).
Abstract: The histone variant H33 is implicated in the formation and maintenance of specialized chromatin structure in metazoan cells H33-containing nucleosomes are assembled in a replication-independent manner by means of dedicated chaperone proteins We previously identified the death domain associated protein (Daxx) and the α-thalassemia X-linked mental retardation protein (ATRX) as H33-associated proteins Here, we report that the highly conserved N terminus of Daxx interacts directly with variant-specific residues in the H33 core Recombinant Daxx assembles H33/H4 tetramers on DNA templates, and the ATRX–Daxx complex catalyzes the deposition and remodeling of H33-containing nucleosomes We find that the ATRX–Daxx complex is bound to telomeric chromatin, and that both components of this complex are required for H33 deposition at telomeres in murine embryonic stem cells (ESCs) These data demonstrate that Daxx functions as an H33-specific chaperone and facilitates the deposition of H33 at heterochromatin loci in the context of the ATRX–Daxx complex
TL;DR: It is shown that fission yeast has more essential genes than budding yeast and that essential genes are more likely than nonessential genes to be present in a single copy, to be broadly conserved and to contain introns.
Abstract: We report the construction and analysis of 4,836 heterozygous diploid deletion mutants covering 98.4% of the fission yeast genome providing a tool for studying eukaryotic biology. Comprehensive gene dispensability comparisons with budding yeast--the only other eukaryote for which a comprehensive knockout library exists--revealed that 83% of single-copy orthologs in the two yeasts had conserved dispensability. Gene dispensability differed for certain pathways between the two yeasts, including mitochondrial translation and cell cycle checkpoint control. We show that fission yeast has more essential genes than budding yeast and that essential genes are more likely than nonessential genes to be present in a single copy, to be broadly conserved and to contain introns. Growth fitness analyses determined sets of haploinsufficient and haploproficient genes for fission yeast, and comparisons with budding yeast identified specific ribosomal proteins and RNA polymerase subunits, which may act more generally to regulate eukaryotic cell growth.
TL;DR: The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes in metazoan cells and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin.
Abstract: The Mediator is an evolutionarily conserved, multiprotein complex that is a key regulator of protein-coding genes. In metazoan cells, multiple pathways that are responsible for homeostasis, cell growth and differentiation converge on the Mediator through transcriptional activators and repressors that target one or more of the almost 30 subunits of this complex. Besides interacting directly with RNA polymerase II, Mediator has multiple functions and can interact with and coordinate the action of numerous other co-activators and co-repressors, including those acting at the level of chromatin. These interactions ultimately allow the Mediator to deliver outputs that range from maximal activation of genes to modulation of basal transcription to long-term epigenetic silencing.
Paris Descartes University1, French Institute of Health and Medical Research2, National Autonomous University of Mexico3, King Saud University4, University of Manchester5, Belfast City Hospital6, Newcastle upon Tyne Hospitals NHS Foundation Trust7, University of Debrecen8, University of Toronto9, Rockefeller University10, Newcastle University11
TL;DR: Findings suggest that auto-Abs against IL- 17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.
Abstract: Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1β, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-β, tumor necrosis factor [α], or transforming growth factor β). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.
TL;DR: The complex design of the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation, and the integral role it plays in key cellular processes is demonstrated.
Abstract: Internal membrane bound structures sequester all genetic material in eukaryotic cells. The most prominent of these structures is the nucleus, which is bounded by a double membrane termed the nuclear envelope (NE). Though this NE separates the nucleoplasm and genetic material within the nucleus from the surrounding cytoplasm, it is studded throughout with portals called nuclear pore complexes (NPCs). The NPC is a highly selective, bidirectional transporter for a tremendous range of protein and ribonucleoprotein cargoes. All the while the NPC must prevent the passage of nonspecific macromolecules, yet allow the free diffusion of water, sugars, and ions. These many types of nuclear transport are regulated at multiple stages, and the NPC carries binding sites for many of the proteins that modulate and modify the cargoes as they pass across the NE. Assembly, maintenance, and repair of the NPC must somehow occur while maintaining the integrity of the NE. Finally, the NPC appears to be an anchor for localization of many nuclear processes, including gene activation and cell cycle regulation. All these requirements demonstrate the complex design of the NPC and the integral role it plays in key cellular processes.
TL;DR: The recently discovered face-processing network of the macaque monkey that consists of six interconnected face-selective regions was targeted and it was found that the anatomical position of a face patch was associated with a unique functional identity.
Abstract: Primates can recognize faces across a range of viewing conditions. Representations of individual identity should thus exist that are invariant to accidental image transformations like view direction. We targeted the recently discovered face-processing network of the macaque monkey that consists of six interconnected face-selective regions and recorded from the two middle patches (ML, middle lateral, and MF, middle fundus) and two anterior patches (AL, anterior lateral, and AM, anterior medial). We found that the anatomical position of a face patch was associated with a unique functional identity: Face patches differed qualitatively in how they represented identity across head orientations. Neurons in ML and MF were view-specific; neurons in AL were tuned to identity mirror-symetrically across views, thus achieving partial view invariance; and neurons in AM, the most anterior face patch, achieved almost full view invariance.
TL;DR: In this Opinion article, some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets are discussed.
Abstract: Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.
TL;DR: Using conditional mutagenesis and viral-mediated gene transfer, it is found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
Abstract: Cocaine-induced alterations in gene expression cause changes in neuronal morphology and behavior that may underlie cocaine addiction. In mice, we identified an essential role for histone 3 lysine 9 (H3K9) dimethylation and the lysine dimethyltransferase G9a in cocaine-induced structural and behavioral plasticity. Repeated cocaine administration reduced global levels of H3K9 dimethylation in the nucleus accumbens. This reduction in histone methylation was mediated through the repression of G9a in this brain region, which was regulated by the cocaine-induced transcription factor DeltaFosB. Using conditional mutagenesis and viral-mediated gene transfer, we found that G9a down-regulation increased the dendritic spine plasticity of nucleus accumbens neurons and enhanced the preference for cocaine, thereby establishing a crucial role for histone methylation in the long-term actions of cocaine.
TL;DR: How well-established risk factors for CVD can originate from inflammation in other tissues is discussed, and possible mechanistic links between skin inflammation and increased risks of obesity or metabolic alterations and CVD are considered.
TL;DR: It is shown that fully differentiated monocyte-derived DCs (Mo-DCs) develop in mice and DC-SIGN/CD209a marks the cells, and the blood monocyte reservoir becomes the dominant presenting cell in response to select microbes, yielding DC- SIGN(+) cells with critical functions of DCs.
TL;DR: It is shown that gain and loss of predicted ubiquitination sites may likely represent a molecular mechanism behind a number of disease‐associatedmutations.
Abstract: Ubiquitination plays an important role in many cellular processes and is implicated in many diseases. Experimental identification of ubiquitination sites is challenging due to rapid turnover of ubiquitinated proteins and the large size of the ubiquitin modifier. We identified 141 new ubiquitination sites using a combination of liquid chromatography, mass spectrometry, and mutant yeast strains. Investigation of the sequence biases and structural preferences around known ubiquitination sites indicated that their properties were similar to those of intrinsically disordered protein regions. Using a combined set of new and previously known ubiquitination sites, we developed a random forest predictor of ubiquitination sites, UbPred. The class-balanced accuracy of UbPred reached 72%, with the area under the ROC curve at 80%. The application of UbPred showed that high confidence Rsp5 ubiquitin ligase substrates and proteins with very short half-lives were significantly enriched in the number of predicted ubiquitination sites. Proteome-wide prediction of ubiquitination sites in Saccharomyces cerevisiae indicated that highly ubiquitinated substrates were prevalent among transcription/enzyme regulators and proteins involved in cell cycle control. In the human proteome, cytoskeletal, cell cycle, regulatory, and cancer-associated proteins display higher extent of ubiquitination than proteins from other functional categories. We show that gain and loss of predicted ubiquitination sites may likely represent a molecular mechanism behind a number of disease-associatedmutations. UbPred is available at http://www.ubpred.org.
TL;DR: Dendritic cells are specialized antigen‐presenting cells and essential mediators of immunity and tolerance and this group of cells is heterogeneous in terms of cell‐surface markers, anatomic location, and function.
Abstract: Dendritic cells (DCs) are specialized antigen-presenting cells and essential mediators of immunity and tolerance. This group of cells is heterogeneous in terms of cell-surface markers, anatomic location, and function. Here, we review the development and function of DCs found in lymphoid and non-lymphoid tissues in the steady state. DC and monocyte lineages originate from a common progenitor, the monocyte and dendritic cell progenitor (MDP). The two cell types diverge when MDPs give rise to monocytes and committed DC progenitors (CDPs) in the bone marrow. CDPs give rise to pre-DCs, which migrate from the bone marrow to lymphoid and non-lymphoid tissues to produce the two major subpopulations of lymphoid tissue DCs and non-lymphoid tissue CD103(+) DCs. Within tissues and during development, DC division and homeostasis are regulated by the hormone Flt3L.
TL;DR: The nuclear pore complex is emerging as an important regulator of gene expression through its influence on the internal architectural organization of the nucleus and its apparently extensive involvement in coordinating the seamless delivery of genetic information to the cytoplasmic protein synthesis machinery.
Abstract: The nuclear pore complex is the key regulator of transport between the cytoplasm and nucleus. Emerging evidence suggests it also regulates gene expression by influencing the internal architecture of the nucleus and by coordinating the delivery of genetic information to the cytoplasmic protein synthesis machinery. Although the nuclear pore complex (NPC) is best known for its primary function as the key regulator of molecular traffic between the cytoplasm and the nucleus, a growing body of experimental evidence suggests that this structure participates in a considerably broader range of cellular activities on both sides of the nuclear envelope. Indeed, the NPC is emerging as an important regulator of gene expression through its influence on the internal architectural organization of the nucleus and its apparently extensive involvement in coordinating the seamless delivery of genetic information to the cytoplasmic protein synthesis machinery.
TL;DR: Evidence linking socio‐economic status (SES) to “downstream” peripheral biology to multiple major biological regulatory systems over the life course is examined, followed by evidence of the resulting cumulative, overall burdens of physiological dysregulation seen among those of lower SES.
Abstract: This chapter focuses on evidence linking socio-economic status (SES) to “downstream” peripheral biology. Drawing on the concept of allostatic load, we examine evidence linking lower SES with greater cumulative physiological toll on multiple major biological regulatory systems over the life course. We begin by reviewing evidence linking lower SES to poorer trajectories of aging in multiple, individual physiological systems, followed by evidence of the resulting cumulative, overall burdens of physiological dysregulation seen among those of lower SES. The role of cumulative physiological dysregulation in mediating SES gradients in morbidity and mortality is then examined. We conclude with discussion of the question of interactions between SES (and other such environmental factors) and genetic endowment, and their potential consequences for patterns of physiological activity—an area of research that appears poised to contribute significantly to our understanding of how social conditions “get under the skin” to affect health and aging.