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Metabolomics-Edited Transcriptomics Analysis (META)

  • Teresa Whei-Mei FanEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

The study of the metabolome or systems biochemical functions in response to external agents such as drugs or toxicants is made possible by recent advances in NMR and mass spectrometry. By coupling the analytical technologies with the stable isotope tracer approach, it is also practical to map changes in metabolic networks with atomic resolution such that metabolic perturbations can be discerned at the enzyme reaction level. This information readily lends its use in guiding transcriptomic analysis for metabolic regulations at the transcriptional level—an approach called “Metabolomics-Edited Transcriptomic Analysis” or META. Two example studies are given to illustrate the use of uniformly 13C-labeled glucose tracer, 13C-isotopomer-based metabolomic analysis, and META for reconstructing metabolic pathways and for discerning their regulatory pathways. The first example describes a hypothetical investigation on the role of a “master” metabolic switch (AMP-activated protein kinase or AMPK) in regulating nucleic acid, lipid, and protein-related metabolism. NMR and GC-MS are complementarily used to obtain quantitative changes in metabolite and 13C-isotopomer profiles in a model cancer cell in response to AMPK activation (induced by AICAR, an adenosine analogue) or AMPK inactivation via siRNA knockdown. Expected findings from META that are consistent with known AMPK-mediated regulations include downregulation or phosphorylation of key proteins involved in the synthesis of fatty acids, phospholipids, and proteins. Scenarios for uncovering metabolic regulations previously unknown or contradictory to known AMPK actions are also given. The second example illustrates a real-world investigation on defining the multitargeted action of selenite in human lung adenocarcinoma A549 cells. The META approach revealed AMPK-mediated downregulation of fatty acid and protein synthesis, in addition to negative regulation of glycolysis, pentose phosphate pathway, Krebs cycle, glutathione synthesis, and nucleotide synthesis, as well as positive regulation of Gln metabolism. The complexity of the selenite action including the induction of opposing regulatory events was resolvable with the integrated metabolomics and transcriptomics approach, which is also generally applicable to any living system including the human body.

Key words

META metabolomics isotopomer analysis AMPK AICAR selenite A549 lung adenocarcinoma 

Abbreviations

ACC

Acetyl CoA carboxylase

ACLY

ATP citrate lyase

aG3P

α-Glycerol-3-phosphate

AICAR

5-Aminoimidazole-4-carboxamide ribonucleoside

aKG

α-Ketoglutarate

AMPK

AMP-activated protein kinase

AXP

Adenine nucleotides

ChREBP

Carbohydrate-response-element-binding protein

CT

Choline transporter

CXP

Cytosine nucleotides

DAG

Diacylglycerol

DAGK

Diacylglycerol kinase

DHAP

Dihydroxyacetone phosphate

eEF2

Eukaryotic elongation factor 2

eIF4E-BP

Eukaryotic initiation factor 4E binding protein

FAS

Fatty acid synthase

FBPase

Fructose bisphosphatase

G6Pase

Glucose-6-phosphatase

G6PDH

Glucose-6-phosphate dehydrogenase

GAP

Glyceraldehyde-3-phosphate

GCL

Glutamyl-cysteinyl ligase

GDH

Glutamate dehydrogenase

Glnase IP

Glutaminase interacting protein

GLU4

Glucose transporter 4

GPAT

Glycerol phosphate acyl transferase

GPC

Glycerophosphorylcholine

GPDH

Glycerol-3-phosphate dehydrogenase

GS

Glycogen synthase

GSH

Reduced glutathione

GSSG

Oxidized glutathione

GXP

Guanine nucleotides

HMGR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

HSQC

Heteronuclear single quantum coherence spectroscopy

iPFK2

Inducible phosphofructokinase 2

KD

Knockdown

LDH

Lactate dehydrogenase

LysoPlase

Lysophospholipase

MCT1

Monocarboxylic acid transporter 1

MDH

Malate dehydrogenase

ME

Malic enzyme

META

Metabolomics-edited transcriptomic analysis

METPA

Metabolomics-edited transcriptomics and proteomics analysis

mTOR

Mammalian target of rapamycin

N transporter

Neutral amino acid transporter

OAA

Oxaloacetate

PABP

Poly(A)-binding protein

PC

Phosphatidylcholines

PCase

Pyruvate carboxylase

P-choline

Phosphorylcholine

PDH

Pyruvate dehydrogenase

PDK

1,3-Phosphoinositide-dependent protein kinase

PE

Phosphatidylethanolamines

PEP

Phosphoenolpyruvate

PEPCK

Phosphoenolpyruvate carboxykinase

PFK

6-Phosphofructo-2-kinase

PI3K

Phosphoinositide-3 kinase

PK

Pyruvate kinase

PKB

Protein kinase B

PKC

Protein kinase C

PL

Phospholipids

PLase

Phospholipase

PPP

Pentose phosphate pathway

S6K

S6 protein kinase

SDH

Succinate dehydrogenase

SREBP

Steroid-regulated-element binding protein

TCA

Trichloroacetic acid

TOCSY

Total correlation spectroscopy

TOP

5′-Tract of oligopyrimidine

TPI

Triosephosphate isomerase

TSC2

Tuberous sclerosis component 2

[U-13C]-Glc

13C labeled glucose

UXP

Uracil nucleotides

Notes

Acknowledgments

This work was supported in part by the National Cancer Institute grant # 1 R01 CA101199-01, NIH Grant Number RR018733 from the National Center for Research Resources, National Science Foundation EPSCoR grant # EPS-0447479, Kentucky Challenge for Excellence, and the Brown Foundation. We thank Dr. Laura Bandura and Ms. Vennila Arumugum for A549 cell culturing, sample processing, and extraction.

Glossary

META

Metabolomics-edited transcriptomics analysis

Systems biology

Holistic and integrated analysis of biological processes as a system, not as individual parts

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of Chemistry, Center for Regulatory and Environmental Analytical Metabolomics (CREAM), and James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA

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