抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

/pdf/transcriptional-architecture-of-the-mammalian-circadian-1a5gaw4u7a.pdf

Transcriptional architecture of the mammalian circadian clock

The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases.

Energy metabolism in the liver

Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet

Disruption of the circadian clock exacerbates metabolic diseases, including obesity and diabetes. We show that histone deacetylase 3 (HDAC3) recruitment to the genome displays a circadian rhythm in mouse liver. Histone acetylation is inversely related to HDAC3 binding, and this rhythm is lost when HDAC3 is absent. Although amounts of HDAC3 are constant, its genomic recruitment in liver corresponds to the expression pattern of the circadian nuclear receptor Rev-erbα. Rev-erbα colocalizes with HDAC3 near genes regulating lipid metabolism, and deletion of HDAC3 or Rev-erbα in mouse liver causes hepatic steatosis. Thus, genomic recruitment of HDAC3 by Rev-erbα directs a circadian rhythm of histone acetylation and gene expression required for normal hepatic lipid homeostasis.

/pdf/a-circadian-rhythm-orchestrated-by-histone-deacetylase-3-4x93xja7bm.pdf

A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism

The nuclear receptor Rev-erbα regulates circadian rhythm and metabolism, but its effects are modest and it has been considered to be a secondary regulator of the cell-autonomous clock. Here we report that depletion of Rev-erbα together with closely related Rev-erbβ has dramatic effects on the cell-autonomous clock as well as hepatic lipid metabolism. Mouse embryonic fibroblasts were rendered arrhythmic by depletion of both Rev-erbs. In mouse livers, Rev-erbβ mRNA and protein levels oscillate with a diurnal pattern similar to that of Rev-erbα, and both Rev-erbs are recruited to a remarkably similar set of binding sites across the genome, enriched near metabolic genes. Depletion of both Rev-erbs in liver synergistically derepresses several metabolic genes as well as genes that control the positive limb of the molecular clock. Moreover, deficiency of both Rev-erbs causes marked hepatic steatosis, in contrast to relatively subtle changes upon loss of either subtype alone. These findings establish the two Rev-erbs as major regulators of both clock function and metabolism, displaying a level of subtype collaboration that is unusual among nuclear receptors but common among core clock proteins, protecting the organism from major perturbations in circadian and metabolic physiology.

/pdf/rev-erba-and-rev-erbb-coordinately-protect-the-circadian-4p60oz0u5n.pdf

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

The nuclear receptor Rev-erbα, a powerful repressor of transcription, is shown to link circadian and thermogenic networks by regulating the function of brown adipose tissue In addition to daily circadian oscillation of body temperature, mammals are able to protect their core body temperature from the cold This study identifies the nuclear receptor Rev-erb , a repressor of transcription, as a link between circadian and thermogenic networks and body temperature rhythmicity through the regulation of brown adipose tissue function Mice exposed to cold fare dramatically better in the morning when Rev-erbα is barely expressed than at five in the afternoon when Rev-erbα is abundant, and deletion of the Rev-erbα gene improves cold tolerance Rev-erbα is shown to function as a physiological repressor of uncoupling protein 1 (Ucp1) in brown adipose tissue, thereby acting to maintain body temperature rhythm in an environmentally responsive manner Circadian oscillation of body temperature is a basic, evolutionarily conserved feature of mammalian biology1 In addition, homeostatic pathways allow organisms to protect their core temperatures in response to cold exposure2 However, the mechanism responsible for coordinating daily body temperature rhythm and adaptability to environmental challenges is unknown Here we show that the nuclear receptor Rev-erbα (also known as Nr1d1), a powerful transcriptional repressor, links circadian and thermogenic networks through the regulation of brown adipose tissue (BAT) function Mice exposed to cold fare considerably better at 05:00 (Zeitgeber time 22) when Rev-erbα is barely expressed than at 17:00 (Zeitgeber time 10) when Rev-erbα is abundant Deletion of Rev-erbα markedly improves cold tolerance at 17:00, indicating that overcoming Rev-erbα-dependent repression is a fundamental feature of the thermogenic response to cold Physiological induction of uncoupling protein 1 (Ucp1) by cold temperatures is preceded by rapid downregulation of Rev-erbα in BAT Rev-erbα represses Ucp1 in a brown-adipose-cell-autonomous manner and BAT Ucp1 levels are high in Rev-erbα-null mice, even at thermoneutrality Genetic loss of Rev-erbα also abolishes normal rhythms of body temperature and BAT activity Thus, Rev-erbα acts as a thermogenic focal point required for establishing and maintaining body temperature rhythm in a manner that is adaptable to environmental demands

/pdf/the-nuclear-receptor-rev-erba-controls-circadian-thermogenic-3znj816xyo.pdf

The nuclear receptor Rev-erbα controls circadian thermogenic plasticity

Circadian rhythms have evolved to anticipate metabolic needs across the 24-hour light/dark cycle. This is accomplished by circadian expression of metabolic genes orchestrated by transcription factors through chromatin remodeling and histone modifications. Our recent genome-wide study on histone deacetylase 3 (HDAC3) in mouse liver provides novel insights into the molecular link between circadian rhythm and hepatic de novo lipogenesis. We found that liver-specific knockout of HDAC3 in adult mouse display severe hepatic steatosis associated with enhanced de novo lipogenesis and increased expression of lipogenic genes. Genome-wide analysis (ChIP-seq) revealed a pronounced circadian pattern of HDAC3 occupancy on genes involved in lipid metabolism, which is inversely related to histone acetylation and RNA polymerase II recruitment at these sites. The cistromes of HDAC3 and its binding partner, nuclear receptor co-repressor (NCoR), significantly overlap with that of Rev-erbα, a nuclear receptor directly involved in the core circadian machinery. Knockout of Rev-erbα in mouse also leads to hepatic steatosis and enhanced de novo lipogenesis. Collectively, these data suggest that the circadian epigenomic remodeling controlled by HDAC3, and largely directed by Rev-erbα, is essential for homeostasis of the lipogenic process in liver.

/pdf/circadian-epigenomic-remodeling-and-hepatic-lipogenesis-2wq62rhg7d.pdf

Anne Bugge

Papers

A Circadian Rhythm Orchestrated by Histone Deacetylase 3 Controls Hepatic Lipid Metabolism

Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function

The nuclear receptor Rev-erbα controls circadian thermogenic plasticity

Circadian Epigenomic Remodeling and Hepatic Lipogenesis: Lessons from HDAC3

Targeted metabolomics reveals alterations in one-carbon metabolism in NAFLD patients