Uma M. Sachdeva

Bio: Uma M. Sachdeva is an academic researcher from Harvard University. The author has contributed to research in topics: Medicine & Esophageal cancer. The author has an hindex of 6, co-authored 17 publications receiving 3063 citations. Previous affiliations of Uma M. Sachdeva include University of Pennsylvania & Columbia University.

ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation

Abstract: Histone acetylation in single cell eukaryotes relies on acetyl-CoA synthetase enzymes that utilize acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure to only low concentrations of extracellular acetate. We show that histone acetylation in mammalian cells is dependent on ATP-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We find that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can impact histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth-factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.

Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability

Abstract: Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.

AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation.

Abstract: Circadian clocks coordinate behavioral and physiological processes with daily light-dark cycles by driving rhythmic transcription of thousands of genes. Whereas the master clock in the brain is set by light, pacemakers in peripheral organs, such as the liver, are reset by food availability, although the setting, or "entrainment," mechanisms remain mysterious. Studying mouse fibroblasts, we demonstrated that the nutrient-responsive adenosine monophosphate-activated protein kinase (AMPK) phosphorylates and destabilizes the clock component cryptochrome 1 (CRY1). In mouse livers, AMPK activity and nuclear localization were rhythmic and inversely correlated with CRY1 nuclear protein abundance. Stimulation of AMPK destabilized cryptochromes and altered circadian rhythms, and mice in which the AMPK pathway was genetically disrupted showed alterations in peripheral clocks. Thus, phosphorylation by AMPK enables cryptochrome to transduce nutrient signals to circadian clocks in mammalian peripheral organs.

Understanding pRb: toward the necessary development of targeted treatments for retinoblastoma

Abstract: Retinoblastoma is a pediatric retinal tumor initiated by biallelic inactivation of the retinoblastoma gene (RB1). RB1 was the first identified tumor suppressor gene and has defined roles in the regulation of cell cycle progression, DNA replication, and terminal differentiation. However, despite the abundance of work demonstrating the molecular function and identifying binding partners of pRb, the challenge facing molecular biologists and clinical oncologists is how to integrate this vast body of molecular knowledge into the development of targeted therapies for treatment of retinoblastoma. We propose that a more thorough genetic understanding of retinoblastoma would inform targeted treatment decisions and could improve outcomes and quality of life in children affected by this disease.

Diurnal rhythms of autophagy: implications for cell biology and human disease.

Abstract: Autophagy is a key mechanism for cell survival under conditions of nutrient limitation. On the organismal level, autophagy is essential for survival of lower eukaryotes during extended periods of starvation, and it is induced in mammals during short-term starvation. As a consequence of the induction of autophagy during short periods of fasting, animals experience diurnal rhythms of autophagy in concert with their circadian cycle. Autophagy has also been identified as a component of the metabolic cycle of yeast, an ultradian rhythm that bears many similarities to the circadian rhythm of plants, flies and mammals. The circadian clock, which is present in almost all mammalian cell types studied to date, temporally regulates expression of multiple genes, gating cell processes such as nutrient uptake, glycolysis, and proliferation, to particular times of day. Whether the circadian clock directly regulates autophagy in mammalian cells, or whether autophagy may play a role in the cycling of mammalian cell clocks is not yet clear. Nevertheless, the relationship between circadian cycles and autophagy is an intriguing area for future study and has implications for multiple human diseases, including aging, neurodegeneration and cancer.

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

Abstract: 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。

AMPK: a nutrient and energy sensor that maintains energy homeostasis

Abstract: AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.