Metabolic regulation of transcription through compartmentalized NAD+biosynthesis

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Abstract

NAD + is an essential molecule for a variety of physiological processes. It is synthesized in distinct subcellular compartments by three different NAD + synthases (NMNATs 1, 2, and 3). We found that compartmentalized NAD + synthesis by NMNATs integrates glucose metabolism and adipogenic transcription during adipocyte differentiation. Adipogenic signaling rapidly induces cytoplasmic NMNAT-2, which competes with nuclear NMNAT-1 for the common substrate, nicotinamide mononucleotide (NMN), leading to a precipitous reduction in nuclear NAD + levels. This inhibits the catalytic activity of PARP-1, an NAD +-dependent enzyme that represses adipogenic transcription by ADP-ribosylating the adipogenic transcription factor, C/EBPβ. Reversal of PARP-1-mediated repression by NMNAT-2-mediated nuclear NAD + depletion in response to adipogenic signals drives adipogenesis. Thus, compartmentalized NAD + synthesis functions as an integrator of cellular metabolism and signal-dependent transcriptional programs.

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Probabilistic modeling of Hi-C contact maps eliminates systematic biases to characterize global chromosomal architecture.

Eitan Yaffe, Amos Tanay (2011)

Hi-C experiments measure the probability of physical proximity between pairs of chromosomal loci on a genomic scale. We report on several systematic biases that substantially affect the Hi-C experimental procedure, including the distance between restriction sites, the GC content of trimmed ligation junctions and sequence uniqueness. To address these biases, we introduce an integrated probabilistic background model and develop algorithms to estimate its parameters and renormalize Hi-C data. Analysis of corrected human lymphoblast contact maps provides genome-wide evidence for interchromosomal aggregation of active chromatin marks, including DNase-hypersensitive sites and transcriptionally active foci. We observe extensive long-range (up to 400 kb) cis interactions at active promoters and derive asymmetric contact profiles next to transcription start sites and CTCF binding sites. Clusters of interacting chromosomal domains suggest physical separation of centromere-proximal and centromere-distal regions. These results provide a computational basis for the inference of chromosomal architectures from Hi-C experiments.

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The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells.

Javier R Revollo, Andrew Grimm, Shin-ichiro Imai (2004)

Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2alpha, in mouse fibroblasts. We found that Nampt was the rate-limiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2alpha recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt- and Sir2alpha-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2alpha and thereby plays an important role in controlling various biological events in mammals.