The human genome is never stagnant. Like checks and balances, internal regulation mechanisms constantly tweak gene expression levels to ensure that bodily function does not go awry. Deviation from standard regulation patterns can be devastating, but defining “normalcy” in terms of gene regulation has proved to be somewhat difficult.
An August 2016 study published in the Science Translational Medicine magazine, therefore ventured to delineate the baseline gene control framework present in a healthy individual’s brain. Establishing the precise characteristics of an undamaged regulation network would aid in the diagnosis of debilitating mental disorders and hint toward most effective treatment measures .
What is an Histone Deacetylase (HDAC)?
Cell nuclei contain DNA in the form of chromatin, spaghetti-like strands sprawling in organized chaos. Core histone molecules dictate varying degrees of chromatin condensation, thereby influencing the level of gene expression. If the tangle is packed too tightly together, enzymes have more difficulty accessing key DNA regions and transcribing the genetic code. What factors influence condensation? Chemical acetyl groups tacked onto core histone tails actually loosen histone’s grip. In contrast, removal of acetyl groups by histone deacetylase (HDAC) enzymes imbues histone with renewed pull .
Overactive HDAC presence is therefore quite problematic; mass elimination of acetyl groups can invigorate histone’s grasp and impede regular gene expression. But for a long time, the science world did not know how normal HDAC activity was supposed to behave in the human brain. Without a healthy paradigm, identifying malicious digression remained an educated shot in the dark .
Enter Martinostat. An HDAC inhibitor, it has the capacity to halt the progression of deacetylation. Working alongside classical positron emission tomography, tracer-level doses of Martinostat can also bind to HDAC complexes in live, healthy subjects and highlight them for the sake of quantification .
The Study Unfolds
Eight volunteers with similarly clean health histories participated in the study. They received injections of radioactively-tinted Martinostat while connected to PET scan monitoring technology. The resulting images revealed increased Martinostat absorption in grey matter (brain tissue consisting of cell bodies, dendrites, and axon terminals) compared to white matter (brain tissue consisting of the actual axons) . Since earlier studies have proven that Martinostat reliably adheres to histone deacetylase complexes, Martinostat’s notable grey matter emphasis suggests loci of elevated HDAC .
While the respective ratios of grey matter to white matter differed between study participants, the values were normalized to allow for simpler comparison. Grey matter displayed nearly twice as much Martinostat-staining as white matter, with particular concentration in the putamen and cerebellum and lower levels in the hippocampus and amygdale. These results painted a groundbreaking picture of HDAC distribution, shedding light onto gene regulation variations in different brain regions .
Surprisingly, the layout of Martinostat binding was extremely consistent from one subject to another. Epigenetic gene regulation was thought to be a roiling, active, and variable process- a conjecture challenged by the predictable pattern evident in this study. HDAC expression is clearly not a haphazard process. With these preliminary maps serving as reference tools, diseased deviation could become easily discernible .
Since tracer Martinostat levels were marginal, the HDAC inhibitor did not actually inhibit any HDAC complexes in early experimental phases. But researchers wanted to observe the treatment in action and determine its subsequent effect on gene expression. Multiplying the Martinostat dosage nearly 1000-fold, they injected human neural progenitor cells and analyzed the mRNA transcript output from various genomic locations to assess degrees of gene expression after treatment .
Results were largely consistent with expectation; Martinostat increased acetylation levels and therefore indirectly elevated expression of genes such as brain-derived neurotrophic factor, early growth response protein 1, cyclin-dependent kinase 5, synaptotagmin, synaptophysin, and progranulin. All of these are linked to memory, neuroplasticity, and optimal neural function .
This experiment established a critical precedent. While scientists have previously recognized the role of histone deacetylases and gene regulation in the development of neural disorders, they did not know the basic design of epigenetic activity in a healthy brain. Martinostat’s binding to HDAC complexes revealed the blazing orientation of healthy epigenetic machinery. Higher dosages were able to inhibit HDAC function, spike acetylation, and improve neural health on multiple fronts.
Martinostat is an exciting, multifaceted tool which will help shed further light on the underpinnings of neural diseases like Alzheimer’s, depression, addiction, schizophrenia, and frontotemporal lobar degeneration .