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

Abstract

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.

• Authors: Jufang Chang, Bin Zhang, Helen Heath, Niels Galjart, Xinyu Wang, Jeffrey Milbrandt
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 50 Pg. 21836-41 (Dec 14 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 21106760 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• CCCTC-Binding Factor
• Cell Cycle Proteins
• Chromosomal Proteins, Non-Histone
• Ctcf protein, mouse
• Repressor Proteins
• NAD

Topics

• Animals
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• CCCTC-Binding Factor
• Cell Cycle Proteins (genetics, metabolism)
• Cells, Cultured
• Chromosomal Proteins, Non-Histone (genetics, metabolism)
• DNA Methylation
• Gene Expression Regulation
• Mice
• NAD (metabolism)
• Neurons (cytology, physiology)
• Promoter Regions, Genetic
• Repressor Proteins (genetics, metabolism)
• Transcription, Genetic
• Cohesins