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Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus

Cellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)–dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases p... Full description

Journal Title: Proceedings of the National Academy of Sciences 14 December 2010, Vol.107(50), p.21836
Main Author: Jufang Chang
Other Authors: Bin Zhang , Helen Heath , Niels Galjart , Xinyu Wang , Jeffrey Milbrandt
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1002130107
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recordid: pnas_s107_50_21836
title: Nicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus
format: Article
creator:
  • Jufang Chang
  • Bin Zhang
  • Helen Heath
  • Niels Galjart
  • Xinyu Wang
  • Jeffrey Milbrandt
subjects:
  • Sciences (General)
ispartof: Proceedings of the National Academy of Sciences, 14 December 2010, Vol.107(50), p.21836
description: Cellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)–dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important roles in this regulation, thus NAD provides a crucial link between metabolism and these cellular signaling processes. Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter. Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus. The loss of these proteins resulted in histone acetylation and methylation changes at this locus consistent with chromatin compaction and gene silencing. Because BDNF is critical for neuronal function, these results suggest that age- or nutrition-associated declines in NAD levels as well as deficits in cohesin function associated with disease modulate BDNF expression and could contribute to cognitive impairment.
language: eng
source:
identifier: ISSN: 0027-8424 ; E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1002130107
fulltext: fulltext_linktorsrc
issn:
  • 0027-8424
  • 00278424
  • 1091-6490
  • 10916490
url: Link


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titleNicotinamide adenine dinucleotide (NAD)–regulated DNA methylation alters CCCTC-binding factor (CTCF)/cohesin binding and transcription at the BDNF locus
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descriptionCellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)–dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important roles in this regulation, thus NAD provides a crucial link between metabolism and these cellular signaling processes. Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter. Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus. The loss of these proteins resulted in histone acetylation and methylation changes at this locus consistent with chromatin compaction and gene silencing. Because BDNF is critical for neuronal function, these results suggest that age- or nutrition-associated declines in NAD levels as well as deficits in cohesin function associated with disease modulate BDNF expression and could contribute to cognitive impairment.
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Cellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)–dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important roles in this regulation, thus NAD provides a crucial link between metabolism and these cellular signaling processes. Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter. Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus. The loss of these proteins resulted in histone acetylation and methylation changes at this locus consistent with chromatin compaction and gene silencing. Because BDNF is critical for neuronal function, these results suggest that age- or nutrition-associated declines in NAD levels as well as deficits in cohesin function associated with disease modulate BDNF expression and could contribute to cognitive impairment.

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Cellular metabolism alters patterns of gene expression through a variety of mechanisms, including alterations in histone modifications and transcription factor activity. Nicotinamide adenine dinucleotide (NAD)–dependent proteins such as poly(ADP ribose) polymerases (PARPs) and sirtuin deacetylases play important roles in this regulation, thus NAD provides a crucial link between metabolism and these cellular signaling processes. Here, we found that lowering NAD levels in mouse primary cortical neurons led to decreased activity-dependent BDNF expression. The altered BDNF transcription occurred independently of Sirt or Parp activities; instead, low NAD levels promoted increased DNA methylation of the activity-dependent BDNF promoter. Increased methylation at this promoter triggered the dissociation of the insulator protein CTCF as well as the accompanying cohesin from the BDNF locus. The loss of these proteins resulted in histone acetylation and methylation changes at this locus consistent with chromatin compaction and gene silencing. Because BDNF is critical for neuronal function, these results suggest that age- or nutrition-associated declines in NAD levels as well as deficits in cohesin function associated with disease modulate BDNF expression and could contribute to cognitive impairment.

pubNational Acad Sciences
doi10.1073/pnas.1002130107
urlhttp://www.pnas.org/content/107/50/21836.abstract
pages21836-21841
date2010-12-14