PMID- 24128087
OWN - NLM
STAT- MEDLINE
DCOM- 20150922
LR  - 20220402
IS  - 1607-842X (Electronic)
IS  - 0891-6934 (Print)
IS  - 0891-6934 (Linking)
VI  - 47
IP  - 4
DP  - 2014 Jun
TI  - Metabolic control of the epigenome in systemic Lupus erythematosus.
PG  - 256-64
LID - 10.3109/08916934.2013.834495 [doi]
AB  - Epigenetic mechanisms are proposed to underlie aberrant gene expression in 
      systemic lupus erythematosus (SLE) that results in dysregulation of the immune 
      system and loss of tolerance. Modifications of DNA and histones require 
      substrates derived from diet and intermediary metabolism. DNA and histone 
      methyltransferases depend on S-adenosylmethionine (SAM) as a methyl donor. SAM is 
      generated from adenosine triphosphate (ATP) and methionine by methionine 
      adenosyltransferase (MAT), a redox-sensitive enzyme in the SAM cycle. The 
      availability of B vitamins and methionine regulate SAM generation. The DNA of SLE 
      patients is hypomethylated, indicating dysfunction in the SAM cycle and 
      methyltransferase activity. Acetyl-CoA, which is necessary for histone 
      acetylation, is generated from citrate produced in mitochondria. Mitochondria are 
      also responsible for de novo synthesis of flavin adenine dinucleotide (FAD) for 
      histone demethylation. Mitochondrial oxidative phosphorylation is the dominant 
      source of ATP. The depletion of ATP in lupus T cells may affect MAT activity as 
      well as adenosine monophosphate (AMP) activated protein kinase (AMPK), which 
      phosphorylates histones and inhibits mechanistic target of rapamycin (mTOR). In 
      turn, mTOR can modify epigenetic pathways including methylation, demethylation, 
      and histone phosphorylation and mediates enhanced T-cell activation in SLE. 
      Beyond their role in metabolism, mitochondria are the main source of reactive 
      oxygen intermediates (ROI), which activate mTOR and regulate the activity of 
      histone and DNA modifying enzymes. In this review we will focus on the sources of 
      metabolites required for epigenetic regulation and how the flux of the underlying 
      metabolic pathways affects gene expression.
FAU - Oaks, Zachary
AU  - Oaks Z
AD  - Division of Rheumatology, Departments of Medicine, Microbiology and Immunology, 
      and Biochemistry and Molecular Biology, State University of New York, Upstate 
      Medical University, College of Medicine , Syracuse, NY , USA.
FAU - Perl, Andras
AU  - Perl A
LA  - eng
GR  - R01 AI072648/AI/NIAID NIH HHS/United States
GR  - U01 AR076092/AR/NIAMS NIH HHS/United States
GR  - AI072648/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20131016
PL  - England
TA  - Autoimmunity
JT  - Autoimmunity
JID - 8900070
RN  - 0 (Histones)
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - EC 2.1.1.- (Histone Methyltransferases)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
SB  - IM
MH  - Animals
MH  - *DNA Methylation
MH  - *Epigenesis, Genetic
MH  - Histone Methyltransferases
MH  - Histone-Lysine N-Methyltransferase/immunology/metabolism
MH  - *Histones/immunology/metabolism
MH  - Humans
MH  - *Lupus Erythematosus, Systemic/genetics/immunology/metabolism
MH  - Lymphocyte Activation
MH  - S-Adenosylmethionine/immunology/metabolism
MH  - T-Lymphocytes/immunology
PMC - PMC4034124
MID - NIHMS580329
OTO - NOTNLM
OT  - Epigenetics
OT  - SLE
OT  - genetics
OT  - metabolism
COIS- Declaration of interest The authors alone are responsible for the content and 
      writing of the paper.
EDAT- 2013/10/17 06:00
MHDA- 2015/09/24 06:00
PMCR- 2014/06/01
CRDT- 2013/10/17 06:00
PHST- 2013/10/17 06:00 [entrez]
PHST- 2013/10/17 06:00 [pubmed]
PHST- 2015/09/24 06:00 [medline]
PHST- 2014/06/01 00:00 [pmc-release]
AID - 10.3109/08916934.2013.834495 [doi]
PST - ppublish
SO  - Autoimmunity. 2014 Jun;47(4):256-64. doi: 10.3109/08916934.2013.834495. Epub 2013 
      Oct 16.