PMID- 23453262
OWN - NLM
STAT- MEDLINE
DCOM- 20140206
LR  - 20240323
IS  - 1873-4847 (Electronic)
IS  - 0955-2863 (Print)
IS  - 0955-2863 (Linking)
VI  - 24
IP  - 8
DP  - 2013 Aug
TI  - Inhibition of proteolysis in histiotrophic nutrition pathways alters DNA 
      methylation and one-carbon metabolism in the organogenesis-stage rat conceptus.
PG  - 1479-87
LID - S0955-2863(12)00305-1 [pii]
LID - 10.1016/j.jnutbio.2012.12.007 [doi]
AB  - Epigenetic modifications, including DNA methylation, contribute to the 
      transcriptional regulation of developmental genes that control growth and 
      differentiation during embryogenesis. The methyl donor, S-adenosylmethionine 
      (SAM), is biosynthesized from methionine and adenosine triphosphate by methionine 
      adenosyltransferase 2a (Mat2a) in the one-carbon (C1) metabolism pathway. SAM 
      biosynthesis requires a steady supply of nutrients, vitamins and cofactors 
      obtained by the developing conceptus through histiotrophic nutrition pathways 
      (HNPs). The visceral yolk sac (VYS) captures proteins and their substrate cargos 
      by receptor-mediated endocytosis and degrades them using lysosomal proteases. We 
      hypothesize that leupeptin, a protease inhibitor, reduces the availability of 
      methionine and C1 substrates, restricting SAM biosynthesis and altering patterns 
      of DNA methylation. Rat conceptuses were exposed to 50 and 100 muM leupeptin in 
      whole embryo culture for periods of 26 h from gestational day (GD) 10 or 6 h on 
      GD11. After 6 h on GD11, the 100-muM leupeptin treatment significantly decreased 
      methionine in embryo (EMB) and VYS, reduced Mat2a protein levels and inhibited 
      Mat2a specific activity, all of which produced a significant 52% reduction of SAM 
      in the VYS. The 50- and 100-muM leupeptin treatments significantly decreased 
      global methylation levels by 6%-9% in EMB and by 11%-15% in VYS following both 6- 
      and 26-h exposure periods. This study demonstrates that HNP disruption alters C1 
      activity and significantly reduces global DNA methylation during organogenesis. 
      Because epigenetic reprogramming is crucial for normal differentiation and 
      growth, these findings suggest a possible mechanism through which nutrients and 
      environmental factors may alter early developmental regulation.
CI  - Copyright (c) 2013. Published by Elsevier Inc.
FAU - Sant, Karilyn E
AU  - Sant KE
AD  - Department of Environmental Health Sciences, University of Michigan, Ann Arbor, 
      Michigan 48109, USA.
FAU - Dolinoy, Dana C
AU  - Dolinoy DC
FAU - Nahar, Muna S
AU  - Nahar MS
FAU - Harris, Craig
AU  - Harris C
LA  - eng
GR  - P30 ES017885/ES/NIEHS NIH HHS/United States
GR  - R01 ES017524/ES/NIEHS NIH HHS/United States
GR  - T32 ES007062/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130228
PL  - United States
TA  - J Nutr Biochem
JT  - The Journal of nutritional biochemistry
JID - 9010081
RN  - 0 (Leupeptins)
RN  - 0 (Micronutrients)
RN  - 7440-44-0 (Carbon)
RN  - 7LP2MPO46S (S-Adenosylmethionine)
RN  - EC 2.5.1.6 (Methionine Adenosyltransferase)
RN  - J97339NR3V (leupeptin)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Carbon/*metabolism
MH  - DNA Methylation/*drug effects
MH  - Embryo Culture Techniques
MH  - *Epigenesis, Genetic
MH  - Female
MH  - Leupeptins/pharmacology
MH  - Methionine Adenosyltransferase/metabolism
MH  - Micronutrients/*administration & dosage
MH  - Molecular Sequence Data
MH  - *Nutritional Physiological Phenomena
MH  - Organogenesis/*drug effects
MH  - Promoter Regions, Genetic
MH  - Proteolysis/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - S-Adenosylmethionine/biosynthesis
PMC - PMC4142195
MID - NIHMS580363
OTO - NOTNLM
OT  - DNA methylation
OT  - Developmental regulation
OT  - Embryonic development
OT  - Histiotrophic nutrition
OT  - Methionine
OT  - One-carbon metabolism
OT  - S-Adenosylmethionine
OT  - Visceral yolk sac
EDAT- 2013/03/05 06:00
MHDA- 2014/02/07 06:00
PMCR- 2014/08/24
CRDT- 2013/03/05 06:00
PHST- 2012/08/14 00:00 [received]
PHST- 2012/11/09 00:00 [revised]
PHST- 2012/12/12 00:00 [accepted]
PHST- 2013/03/05 06:00 [entrez]
PHST- 2013/03/05 06:00 [pubmed]
PHST- 2014/02/07 06:00 [medline]
PHST- 2014/08/24 00:00 [pmc-release]
AID - S0955-2863(12)00305-1 [pii]
AID - 10.1016/j.jnutbio.2012.12.007 [doi]
PST - ppublish
SO  - J Nutr Biochem. 2013 Aug;24(8):1479-87. doi: 10.1016/j.jnutbio.2012.12.007. Epub 
      2013 Feb 28.