Harry MacKay Harry MacKay

Developmental Epigenetics of the Hypothalamus

After I finished my Ph.D. in Neuroscience, I moved to Houston, Texas to join Dr. Robert Waterland’s lab at the Baylor College of Medicine as a postdoctoral fellow. The intellectual backdrop for my Ph.D. work was a concept called ‘developmental programming’, which refers to the ability for the early-life environment to exert a long-lasting effect on metabolism. Importantly, the critical window for developmental programming is narrow, and once it has passed, things are essentially fixed in place. One could spend a career flinging challenges at that window, but a more fundamental question is why that window exists at all, and how does it close? This is the basic question I am answering during my postdoc. In the brain, one way to look at this is to consider that neurons begin life as solitary units with many possibilities, and over development they gradually become more and more specialized. They build connections with other neurons, they acquire a profile of gene expression that is more narrow and mature, and ultimately settle into a comfortable and predictable adult life. In the part of the brain I’m interested in, things are more or less settled by the time of weaning (in mice).

A narrowing of options can imply a narrowing of available tools. In this analogy, ‘tools’ refers to the genes being expressed. You see, the list of genes available to a given cell becomes narrower and narrower as it matures. This allows cell types to become specialized, but it also closes the door on further development, since development itself relies on a certain pattern of gene expression. Epigenetics refers to a pattern of cell type specific, mitotically heritable changes in gene expression potential that does not affect the DNA code itself. Epigenetics may well be the key to both normal development, and also developmental programming. What are the cell type-specific epigenetic signatures of important populations of neurons in the brain’s appetite circuits? How do these signatures change over development and how do these changes relate to the critical window? What happens when you try to block these changes? These questions and more are the subject of my postdoctoral work, and they have the potential to contribute to the fundamental question of my research career “aside from genetics, why do some people become overweight and others don’t?”. Stay tuned…

In the Waterland lab, I am coupling neuroanatomically precise microdissection techniques with FACS and cell type-specific genetic manipulation to study the developmental epigenetics of the hypothalamic feeding circuitry in unprecedented detail. These techniques allow us to interrogate DNA methylation, chromatin conformation, and gene expression with an extremely high level of cell type specificity, and with this we hope to gain insights into the normal neuroepigenetic development of hypothalamus. This in turn will help us to understand how these normal developmental processes can go awry when ideal environmental conditions are not met (i.e. in cases of maternal obesity, undernutrition, or endocrine disruptor exposure).

Relevant papers:

Klein, MO., MacKay, H., Edwards, A., Park, S-B., Kiss, ACI., Felicio, LF., Abizaid, A. POMC and NPY mRNA expression during development is increased in rat offspring brains from mothers fed with a high-fat diet. International Journal of Developmental Neuroscience, 2017

MacKay, H., Heindel, JJ., Ross, MG., Waterland, RA. Meeting Summary: The inaugural meeting of the US DOHaD society. Environmental Epigenetics, 2017

MacKay, H and Abizaid A. Embryonic development of the hypothalamic feeding circuitry: Transcriptional, nutritional, and hormonal influences. Molecular Metabolism, 2014


More Posts