A fundamental challenge in the field of neuroscience is understanding the link between environmental signals and the transcriptional response underlying the resulting long term changes in neuronal function. Neurons uniquely require highly dynamic and temporal control of gene activation for processes ranging from memory formation to synapse formation during development. Whether specific genes are ultimately activated is highly dependent on the epigenetic regulation of transcription through the histone proteins that control DNA accessibility and regulate transcription. The importance of this `histone code' or is becoming increasingly appreciated in neuroscience, from its function in memory storage to its involvement in neurological disorders. My goal is to elucidate the histone code that controls the nervous system with the aim of better understanding the regulation of transcription both in normal neurons and in mental and developmental disorders. The research I propose encompasses all aspects of histone regulation and has a strong foundation in the work developed and performed in the Allis laboratory on histone modifications and variants. During the training period, I will continue my work on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also investigate the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will begin to investigate the role of histone modifications such as crotonylation that have not yet been examined the context neuronal gene expression but provide the complex transcriptional regulation needed to achieve the varied functions of the nervous system. During this mentored period, I propose to develop and expand on new tools I will use to during the independent phase of the award. In addition, I will learn a combination of computational and genomics techniques and biochemical approaches that will set me apart from the field and provide me with the skills necessary to work at the intersection of epigenetics and neuroscience. With the development of new tools and acquisition of valuable skills that I describe in the training plan of award, I will be a unique position to apply diverse approaches to reveal new insights into the role of histones in regulating transcription of genes critical for neuronal function. This research will allow for the histone code of gene activation to be applied to information storage in the brain, providing new insights into mechanism underlying neuronal function and the epigenetic causes of neurological disorders.
The nervous system requires tight control of transcription for processes ranging from brain development to memory formation. The field of epigenetics seeks to understand how changes to genes transcription occur. I propose to apply the tools and techniques used for the study of epigenetics to the field of neuroscience, both to provide new insights into the mechanisms underlying memory formation as well as new treatments for Fragile X Syndrome and other disorders affecting mental health.
| Korb, Erica; Herre, Margaret; Zucker-Scharff, Ilana et al. (2017) Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition. Cell 170:1209-1223.e20 |
