title: 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.affiliation: Department of Genetics, and Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jufang
authors.initials: J
authors.lastname: Chang
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Helen
authors.initials: H
authors.lastname: Heath
authors.forename: Niels
authors.initials: N
authors.lastname: Galjart
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005786:Gene Expression Regulation; D051379:Mice; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D009243:NAD; D012097:Repressor Proteins; D000097722:Cohesins; C000619698:Ctcf protein, mouse