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. B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. It plays important roles in regulating neurogenesis, synaptic plasticity, and neuronal survival-functions that are vital to learning, memory, and cognition (1, 2). In the CNS, BDNF transcription is regulated by neuronal activity with high expression in the hippocampus and cortex (3, 4). The BDNF gene contains multiple promoters that generate transcripts containing different noncoding exons spliced to a common single coding exon (4). Of the multiple BDNF mRNAs, transcription initiated from BDNF promoter IV is dramatically activated in neurons treated with KCl, which causes membrane depolarization and subsequent influx of calcium (5, 6). In addition to calcium signaling pathways, BDNF transcription is regulated epigenetically by DNA methylation and subsequent chromatin remodeling. Specifically, DNA methylation at promoter IV is involved in silencing BDNF gene expression via transcriptional repressor methyl-CpG-binding protein (MeCP2) (5-7). Abnormal BDNF transcription resulting from aberrant occupancy of methylated DNA binding sites in its promoter has been implicated in the etiology of Rett syndrome (8), and other abnormalities in BDNF are associated with neurodegenerative disorders, including Huntington, Alzheimer, and Parkinson diseases (2), as well as psychiatric disorders such as depression and schizophrenia (1).Age-associated declines in BDNF levels are thought to contribute to impaired cognitive performance in older individuals (9), as are age-related changes in metabolism (10). Nicotinamide adenine dinucleotide (NAD) is a key molecule that links the metabolic state of the cell with gene expression and cell functions. These l...

Use of engineered bone marrow stem cells to deliver brain derived neurotrophic factor under the control of a tetracycline sensitive response element in experimental allergic encephalomyelitis

“…It is possible that in our system, BDNF maintains the NAD level in the neurons; however the mechanism is not the same for the maintenance of the NAD level in activated infiltrated cells. Interestingly Chang et al, 2010 recently reported that the NAD levels modulate BDNF expression (Chang et al, 2010). Together our results are consistent with the hypothesis that BDNF may reduce the severity of EAE by preventing the depletion of NAD levels in inflammation and protecting neuronal cells.…”

An NAD + -dependent transcriptional program governs self-renewal and radiation resistance in glioblastoma

“…However, NAMPT is highly expressed in several cancers, and features of cancer cells, including proliferation, invasion, and tumor growth, exhibit a dependence on NAD + (9)(10)(11). In noncancer cells, NAD + plays a critical role in transcriptional control, providing a metabolic basis for epigenetic reprogramming (12)(13)(14)(15)(16). Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13)(14)(15).…”

“…Enzymes using NAD + as a cofactor, including the sirtuins and poly-ADP ribosyl transferases, regulate transcription factor activity and chromatin structure (13)(14)(15). Additionally, NAD + can control transcription by altering DNA methylation in neurons (12). However, in glioblastoma, little is known about NAD + -dependent transcriptional events and whether these events impact malignant behavior and therapy response.…”

Connecting Phytochemicals, Epigenetics, and Healthy Aging

“…This structural restriction of silenced chromatin on gene expression can be overcome by chromatin writer, reader, and eraser enzyme complexes, which remodel nucleosomes along the DNA or reversibly modify (acetylation, phosphorylation, ubiquitylation, glycosylation, and sumoylation) histones on lysine, arginine, serine, or threonine residues of amino-terminal histone tails and establish specific chromatin states involved in transcription [20][21][22]. One critical facet of histone and DNA modifying enzymes is that their activity also depends on intracellular levels of essential metabolites [acetyl-coA, Fe, ketoglutarate, nicotinamide adenine dinucleotide (NAD) + , and SAM], the concentrations of which are tightly linked to global cellular metabolism and energy levels [23][24][25][26][27][28][29]. Gene regulation is thus linked to the metabolic status of cells ( Fig.…”