Lysine acetylation: the tale of a modification from transcription regulation to metabolism

Reversible lysine acetylation is an important modification involved in the regulation of gene expression. Acetyl-CoA and NAD+ are major determinants of this modification, NAD+ levels being regulated by the cellular redox status. Recent reports have shown that lysine acetylation also regulates metabolic processes, thus linking the central metabolic process to gene expression

Tuning acetylation levels with HAT activators: Therapeutic strategy in neurodegenerative diseases

International audienc

ATP driven clathrin dependent entry of carbon nanospheres prefer cells with glucose receptors

Abstract Background Intrinsically fluorescent glucose derived carbon nanospheres (CSP) efficiently enter mammalian cells and also cross the blood brain barrier (BBB). However, the mechanistic details of CSP entry inside mammalian cells and its specificity are not known. Results In this report, the biochemical and cellular mechanism of CSP entry into the living cell have been investigated. By employing confocal imaging we show that CSP entry into the mammalian cells is an ATP-dependent clathrin mediated endocytosis process. Zeta potential studies suggest that it has a strong preference for cells which possess high levels of glucose transporters such as the glial cells, thereby enabling it to target individual organs/tissues such as the brain with increased specificity. Conclusion The endocytosis of Glucose derived CSP into mammalian cells is an ATP dependent process mediated by clathrin coated pits. CSPs utilize the surface functional groups to target cells containing glucose transporters on its membrane thereby implicating a potential application for specific targeting of the brain or cancer cells.</p

Intrinsically fluorescent carbon nanospheres as a nuclear targeting vector: delivery of membrane-impermeable molecule to modulate gene expression in vivo

In this report, we demonstrate glucose-derived carbon nanospheres(1) to be an emerging class of intracellular carriers. The surfaces of these spheres are highly functionalized and do not need any further modification. Besides, the intrinsic fluorescence property of carbon nanospheres helps in tracking their cellular localization without any additional fluorescent tags. The spheres are found to target the nucleus of the mammalian cells, causing no toxicity. Interestingly, the in vivo experiments show that these nanospheres have an important ability to cross the blood-brain barrier and localize in the brain besides getting localized in the liver and the spleen. There is also evidence to show that they are continuously being removed from these tissues over time. Furthermore, these nanospheres were used as a carrier for the membrane-impermeable molecule CTPB (N-(4-chloro-3-trifluoromethylphenyl)-2-ethoxybenzamide), the only known small-molecule activator of histone acetyltransferase (HAT) p300.(2) Biochemical analyses such as Western blotting, immunohistochemistry, and gene expression analysis show the induction of the hyperacetylation of histone acetyltransferase (HAT) p300 (autoacetylation) as well as histones both in vitro and in vivo and the activation of HAT-dependent transcription upon CTPB delivery. These results establish an alternative path for the activation of gene expression mediated by the induction of HAT activity instead of histone deacetylase (HDAC) inhibition

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

International audienc

Multifunctional carbon nanospheres with magnetic and luminescent probes: probable brain theranostic agents

Multi-functional carbon nanospheres with magnetic Prussian blue nanoparticles and luminescent lanthanide ions have been prepared. The negatively charged surface of the glucose derived carbon sphere facilitates the nucleation of Prussian blue nanoparticles on its surface. The luminescent lanthanide probes were attached to the surface of the carbon sphere through a benzene tricarboxylic acid linker. These multifunctional hybrid organic–inorganic composites are superparamagnetic and show enhanced luminescent properties. Their ability to cross the blood–brain barrier (enter the brain cell nucleus with no animal toxicity) in a mouse model indicate that these nanocomposites are promising theranostic agents for the treatment of brain diseases

Chemical Biology Research in India

Chemical biology, as the terminology suggests, is the intertwining of chemistry and biology. However, the exact definition of chemical biology has been constantly debated among the researchers working at the interface of chemistry and biology. One of the major differences between the closely related fields of biochemistry and chemical biology is that the former is more relevant to the actual physiological scenario, whereas the latter has a synthetic feel to it. Thus, exploring biology with the aid of chemical tools can be considered to be the main philosophy of chemical biology. The science of chemical biology in the present form is only about 2 decades old, and hence the successes and failures in this area are more in the limelight than many other fields of science. All over the world, there are active initiatives to merge this new area of research into the scientific mainstream. Universities such as MIT, Harvard, RIKEN, and McGill have full-fledged departments dedicated to chemical biology. Perhaps the earliest research institute in the world dedicated to chemical biology was the CSIR-Indian Institute of Chemical Biology in Kolkata, India. The 75-year-old research institute was reoriented and renamed in 1982 to its present form to explore the chemistry of life—with chemical and biochemical tools. In India, this exciting area of research has spread beyond this institute, and in this In Focus article we shall highlight the status of chemical biology research in India with respect to its past, present, and future. Although work at the interface of chemistry and biology is widespread in India, we will largely focus on institutions that use chemical tools to explore biology

J. Neurosci.

Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases