4.1.4: Child Nutrition and the Epigenome

Child nutrition and the epigenome

Whether or not your parents knew the science behind it, telling you to eat your veggies as a kid really does make you healthier and stronger—at least your DNA, that is. [Image: U.S. Department of Agriculture, https://goo.gl/tpyYzA, CC BY 2.0, https://goo.gl/BRvSA7]

The old adage “you are what you eat” might be true on more than just a physical level: The food you choose (and even what your parents and grandparents chose) is reflected in your own personal development and risk for disease in adult life (Wells, 2003). Nutrients can reverse or change DNA methylation and histone modifications, thereby modifying the expression of critical genes associated with physiologic and pathologic processes, including embryonic development, aging, and carcinogenesis. It appears that nutrients can influence the epigenome either by directly inhibiting enzymes that catalyze DNA methylation or histone modifications, or by altering the availability of substrates necessary for those enzymatic reactions. For example, rat mothers fed a diet low in methyl group donors during pregnancy produce offspring with reduced DNMT-1 expression, decreased DNA methylation, and increased histone acetylation at promoter regions of specific genes, including the glucocorticoid receptor, and increased gene expression in the liver of juvenile offspring (Lillycrop, Phillips, Jackson, Hanson, & Burdge, 2005) and adult offspring (Lillycrop et al., 2007). These data suggest that early life nutrition has the potential to influence epigenetic programming in the brain not only during early development but also in adult life, thereby modulating health throughout life. In this regard, nutritional epigenetics has been viewed as an attractive tool to prevent pediatric developmental diseases and cancer, as well as to delay aging-associated processes.

The best evidence relating to the impact of adverse environmental conditions development and health comes from studies of the children of women who were pregnant during two civilian famines of World War II: the Siege of Leningrad (1941–44) (Bateson, 2001) and the Dutch Hunger Winter (1944–1945) (Stanner et al., 1997). In the Netherlands famine, women who were previously well nourished were subjected to low caloric intake and associated environmental stressors. Women who endured the famine in the late stages of pregnancy gave birth to smaller babies (Lumey & Stein, 1997) and these children had an increased risk of insulin resistance later in life (Painter, Roseboom, & Bleker, 2005). In addition, offspring who were starved prenatally later experienced impaired glucose tolerance in adulthood, even when food was more abundant (Stanner et al., 1997). Famine exposure at various stages of gestation was associated with a wide range of risks such as increased obesity, higher rates of coronary heart disease, and lower birth weight (Lumey & Stein, 1997). Interestingly, when examined 60 years later, people exposed to famine prenatally showed reduced DNA methylation compared with their unexposed same-sex siblings (Heijmans et al., 2008).

Epigenetic regulation of learning and memory

Neural plasticity is the change of neural pathways and synapses which allows for our ability to learn new things and remember them. [Image: Gerry Shaw, https://goo.gl/JBqlY7, CC BY-SA 3.0, https://goo.gl/eLCn2O]

Memories are recollections of actual events stored within our brains. But how is our brain able to form and store these memories? Epigenetic mechanisms influence genomic activities in the brain to produce long-term changes in synaptic signaling, organization, and morphology, which in turn support learning and memory (Day & Sweatt, 2011).

Neuronal activity in the hippocampus of mice is associated with changes in DNA methylation (Guo et al., 2011), and disruption to genes encoding the DNA methylation machinery cause learning and memory impairments (Feng et al., 2010). DNA methylation has also been implicated in the maintenance of long-term memories, as pharmacological inhibition of DNA methylation and impaired memory (Day & Sweatt, 2011; Miller et al., 2010). These findings indicate the importance of DNA methylation in mediating synaptic plasticity and cognitive functions, both of which are disturbed in psychological illness.

Changes in histone modifications can also influence long-term memory formation by altering chromatin accessibility and the expression of genes relevant to learning and memory. Memory formation and the associated enhancements in synaptic transmission are accompanied by increases in histone acetylation (Guan et al., 2002) and alterations in histone methylation (Schaefer et al., 2009), which promote gene expression. Conversely, a neuronal increase in histone deacetylase activity, which promotes gene silencing, results in reduced synaptic plasticity and impairs memory (Guan et al., 2009). Pharmacological inhibition of histone deacetylases augments memory formation (Guan et al., 2009; Levenson et al., 2004), further suggesting that histone (de)acetylation regulates this process.

In humans genetic defects in genes encoding the DNA methylation and chromatin machinery exhibit profound effects on cognitive function and mental health (Jiang, Bressler, & Beaudet, 2004). The two best-characterized examples are Rett syndrome (Amir et al., 1999) and Rubinstein-Taybi syndrome (RTS) (Alarcon et al., 2004), which are profound intellectual disability disorders. Both MECP2 and CBP are highly expressed in neurons and are involved in regulating neural gene expression (Chen et al., 2003; Martinowich et al., 2003).

Rett syndrome patients have a mutation in their DNA sequence in a gene called MECP2. MECP2 plays many important roles within the cell: One of these roles is to read the DNA sequence, checking for DNA methylation, and to bind to areas that contain methylation, thereby preventing the wrong proteins from being present. Other roles for MECP2 include promoting the presence of particular, necessary, proteins, ensuring that DNA is packaged properly within the cell and assisting with the production of proteins. MECP2 function also influences gene expression that supports dendritic and synaptic development and hippocampus-dependent memory (Li, Zhong, Chau, Williams, & Chang, 2011; Skene et al., 2010). Mice with altered MECP2 expression exhibit genome-wide increases in histone acetylation, neuron cell death, increased anxiety, cognitive deficits, and social withdrawal (Shahbazian et al., 2002). These findings support a model in which DNA methylation and MECP2 constitute a cell-specific epigenetic mechanism for regulation of histone modification and gene expression, which may be disrupted in Rett syndrome.

RTS patients have a mutation in their DNA sequence in a gene called CBP. One of these roles of CBP is to bind to specific histones and promote histone acetylation, thereby promoting gene expression. Consistent with this function, RTS patients exhibit a genome-wide decrease in histone acetylation and cognitive dysfunction in adulthood (Kalkhoven et al., 2003). The learning and memory deficits are attributed to disrupted neural plasticity (Korzus, Rosenfeld, & Mayford, 2004). Similar to RTS in humans, mice with a mutation of CBP perform poorly in cognitive tasks and show decreased genome-wide histone acetylation (for review, see Josselyn, 2005). In the mouse brain CBP was found to act as an epigenetic switch to promote the birth of new neurons in the brain. Interestingly, this epigenetic mechanism is disrupted in the fetal brains of mice with a mutation of CBP, which, as pups, exhibit early behavioral deficits following removal and separation from their mother (Wang et al., 2010). These findings provide a novel mechanism whereby environmental cues, acting through histone modifying enzymes, can regulate epigenetic status and thereby directly promote neurogenesis, which regulates neurobehavioral development.

Together, these studies demonstrate that misregulation of epigenetic modifications and their regulatory enzymes is capable of orchestrating prominent deficits in neuronal plasticity and cognitive function. Knowledge from these studies may provide greater insight into other mental disorders such as depression and suicidal behaviors.

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