Working Out: The Molecular Biology of Exercise.

The many health benefits of exercise are well-known. Conversely, the pathologies associated with a sedentary lifestyle are also well-documented. However, science and medicine have only recently begun to explain how exercise does what it does. Here, I discuss recent insight into the biochemical mechanisms underlying the benefits of exercise and the pathologies of inactivity.

The little elongation complex functions at initiation and elongation phases of snRNA gene transcription.

The small nuclear RNA (snRNA) genes have been widely used as a model system for understanding transcriptional regulation due to the unique aspects of their promoter structure, selectivity for either RNA polymerase (Pol) II or III, and because of their unique mechanism of termination that is tightly linked with the promoter. Recently, we identified the little elongation complex (LEC) in Drosophila that is required for the expression of Pol II-transcribed snRNA genes. Here, using Drosophila and mammalian systems, we provide genetic and molecular evidence that LEC functions in at least two phases of snRNA transcription: an initiation step requiring the ICE1 subunit, and an elongation step requiring ELL.

The little elongation complex regulates small nuclear RNA transcription.

Eleven-nineteen lysine-rich leukemia (ELL) participates in the super elongation complex (SEC) with the RNA polymerase II (Pol II) CTD kinase P-TEFb. SEC is a key regulator in the expression of HOX genes in mixed lineage leukemia (MLL)-based hematological malignancies, in the control of induced gene expression early in development, and in immediate early gene transcription. Here, we identify an SEC-like complex in Drosophila, as well as a distinct ELL-containing complex that lacks P-TEFb and other components of SEC named the "little elongation complex" (LEC). LEC subunits are highly enriched at RNA Pol II-transcribed small nuclear RNA (snRNA) genes, and the loss of LEC results in decreased snRNA expression in both flies and mammals. The specialization of the SEC and LEC complexes for mRNA and snRNA-containing genes, respectively, suggests the presence of specific classes of elongation factors for each class of genes transcribed by RNA polymerase II.

The Brave New World of Gene Editing and Molecular Medicine.

Gene therapy has long been a promise of molecular biology. So far, that promise has largely been unrealized. The advent of gene editing using technology adapted from bacteria may finally usher in the era of gene therapy.

Pharmacogenomics: What the Doctor Ordered?

About half a million adverse drug reactions are reported in the US each year that result in disability, hospitalization or death. The efficacy or toxicity of a drug in a patient can be strongly influenced by their genetics as well as environment. Application of genomics to clinical pharmacology, "pharmacogenomics," promises to transform patient care and health resource utilization in the coming decade.

Hungering for Immortality.

Beyond avoiding risky behavior-smoking, substance abuse, obesity-and embracing healthy habits like exercise, a balanced diet, and non-obese body weight, are there things we each do today to significantly extend our lifespan? Caloric restriction is the only behavioral intervention consistently shown to extend both mean and maximal lifespan across a wide range of species. In most cases, the lifespan extension is accompanied by a marked delay in the onset of age-associated disease and infirmity.

HP1a: a structural chromosomal protein regulating transcription.

Heterochromatin protein 1 (HP1a in Drosophila) is a conserved eukaryotic chromosomal protein that is prominently associated with pericentric heterochromatin and mediates the concomitant gene silencing. Mechanistic studies implicate HP1 family proteins as 'hub proteins,' able to interact with a variety of chromosomal proteins through the chromo-shadow domain (CSD), as well as to recognize key histone modification sites [primarily histone H3 di/trimethyl Lys9 (H3K9me2/3)] through the chromodomain (CD). Consequently, HP1 has many important roles in chromatin architecture and impacts both gene expression and gene silencing, utilizing a variety of mechanisms. Clearly, HP1 function is altered by context, and potentially by post-translational modifications (PTMs). Here, we report on recent ideas as to how this versatile protein accomplishes its diverse functions.

À la recherche du temps perdu: Smoking and Genomic Imprinting.

Tobacco smoking is the largest cause of preventable mortality and morbidity in the United States. Many of the pathological consequences of smoking result from mutations, but gene expression can also be modulated by genomic imprinting mediated by DNA methylation-so-called "epigenetic" regulation. Since genomic imprints, unlike gene mutations, can be reversed, it is of great interest what smoking-related imprints mean for smoking-related pathologies in smokers and their children, and the potential for imprint-targeted diagnostics and therapeutics.

Direct-to-Consumer Genomics: Harmful or Empowering?: It is important to stress that genetic risk is not the same as genetic destiny.

The price of whole-genome sequencing is now within the budget of the average American consumer. This has resulted in the commercialization of genome sequencing for a variety of applications, including health-related risk assessment. Direct-to-consumer marketing of personal DNA sequence information uncouples the generation of personal health-related data from the physician-patient relationship. Here, I discuss the status of consumer genomics and the current and potential concerns about bypassing physicians in the analysis and interpretation of personal genomic information and subsequent health care decision-making.

Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor.

The extracellular nuclear proteins, histone H4 (H4) and high mobility group box 1 (HMGB1), released by injured cells during the activation of inflammation and coagulation pathways provoke potent inflammatory responses through interaction with pathogen-related pattern recognition receptors (ie, Toll-like receptors [TLRs] and receptor for advanced glycation end products [RAGE]) present on vascular and innate immune cells. Inorganic polyphosphate (polyP) has emerged as a key modulator of coagulation and inflammation. Here, we demonstrate that polyP binds to both H4 and HMGB1 with high affinity, thereby dramatically potentiating their proinflammatory properties in cellular and in vivo models. By using small interfering RNA knockdowns, pharmacologic inhibitors and extracellular domains of the receptors TLR2, TLR4, RAGE, and P2Y1 as competitive inhibitors, we demonstrate that polyP amplifies H4- and HMGB1-mediated inflammatory signaling in human umbilical vein endothelial cells specifically through interaction with the RAGE and P2Y1 receptors, thereby eliciting intracellular Ca(2+) release. Finally, we demonstrate that the natural anticoagulant protease, activated protein C, potently inhibits polyP-mediated proinflammatory effects of both nuclear proteins in cellular and in vivo systems.

Epigenetics: modifying the genetic blueprint.

The sequence of the human genome represents our genetic blueprint. While it is now possible to draw direct connections between specific DNA sequences and specific physical features and to predict disease risk, the effects of certain genes can be masked by a process called "epigenetics." Here, I summarize our current understanding of epigenetics and it affects gene expression, with impacts on health and aging.

The Nobel Path of Cellular Proteins.

For one week every October, the world awaits the Nobel Prize announcements. While much publicity is focused on the laureates, the awards in the sciences also recognize high-impact fields of research. The 2013 Nobel Prize in Physiology or Medicine honored three scientists whose research defined the mechanisms by which cellular vesicles sort proteins to their final destinations. This research shaped a modern understanding of how protein sorting controls cellular identity and function.

Drosophila GGA model: an ultimate gateway to GGA analysis.

Golgi-localized, γ-ear-containing, ADP ribosylation factor-binding (GGA) proteins are monomeric adaptors implicated in clathrin-mediated vesicular transport between the trans Golgi network and endosomes, characterized mainly from cell culture analysis of lysosomal sorting. To provide the first demonstration of GGA's role in vivo, we used Drosophila which has a single GGA and a single lysosomal sorting receptor, lysosomal enzyme receptor protein (LERP). Using RNAi knockdowns, we show that the Drosophila GGA is required for lysosomal sorting. We further identified authentic components of the Drosophila lysosomal sorting system--the sorting receptor LERP, the sorting adaptor GGA and the lysosomal cargo cathepsins B1, D and L--to show that GGA depletion results in lysosomal dysfunction. Abnormal lysosomal morphology, missorting of lysosomal cathepsins and impaired lysosomal proteolysis show disturbed LERP trafficking after GGA depletion. GGA is highly expressed in the mushroom bodies and the pigment cells of the retina, and increasing or decreasing the levels of GGA in the eyes leads to retinal defects. Reduced GGA levels also enhance an eye defect caused by overexpression of the autophagy-associated protein Blue cheese (Bchs), implicating GGA in autophagic processes. This shows that Drosophila provides an excellent whole-animal model to gain new insights into the function of GGA in the physiological environment of a multicellular organism.

The role of MOF in the ionizing radiation response is conserved in Drosophila melanogaster.

In Drosophila, males absent on the first (MOF) acetylates histone H4 at lysine 16 (H4K16ac). This acetylation mark is highly enriched on the male X chromosome and is required for dosage compensation in Drosophila but not utilized for such in mammals. Recently, we and others reported that mammalian MOF, through H4K16ac, has a critical role at multiple stages in the DNA damage response (DDR) and double-strand break repair pathways. The goal of this study was to test whether mof is similarly required for the response to ionizing radiation (IR) in Drosophila. We report that Drosophila mof mutations in males and females, as well as mof knockdown in SL-2 cells, reduce post-irradiation survival. MOF depletion in SL-2 cells also results in an elevated frequency of metaphases with chromosomal aberrations, suggesting that MOF is involved in DDR. Mutation in Drosophila mof also results in a defective mitotic checkpoint, enhanced apoptosis, and a defective p53 response post-irradiation. In addition, IR exposure enhanced H4K16ac levels in Drosophila as it also does in mammals. These results are the first to demonstrate a requirement for MOF in the whole animal IR response and suggest that the role of MOF in the response to IR is conserved between Drosophila and mammals.

Telomeres, cancer & aging: live long & prosper?

Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends. Drugs that selectively fray the ends of cancer cell chromosomes would be potent and general anti-cancer therapies. Here, I summarize data on the role of chromosome ends in cellular and organismal aging.

Seed and soil: A conceptual framework of metastasis for clinicians.

Most mortality from cancer is secondary to metastasis. Metastasis refers both to the process by which tumor cells establish themselves at organs distinct from where they originated and to the life-threatening lesions themselves. Metastases are often resistant to conventional therapies, highlighting a key distinction between these progeny lesions and the primary tumor from which they arose. Here, we summarize recent advances in understanding and targeting primary tumors and the mechanisms and therapeutic challenges of metastasis.