16 Divinity Ave, Rm 4005B
Cambridge, MA 02138
We use quantitative methods to understand interactions between genes within neurons. Our DNA represents the full library of genetic information each of us inherits from our parents. We inherit two copies of each gene, one from our mother and one from our father. Typically, the two copies are treated equally in the cell. However, my lab studies a unique class of “imprinted genes,” in which only one parental copy is active (“expressed”) while the other is inactive (“silenced”). Many imprinted genes are expressed in the brain and regulate organismal behavior, growth, cognition, and socialization. The influence of genomic imprinting on brain function may be far greater than previously appreciated; increasing evidence implicates aberrations in imprinted genes in neurodevelopmental and neurological disorders. My lab seeks to delineate the roles of imprinted genes in the brain and, in the long term, achieve insights into the molecular and cellular mechanisms of imprinted disorders. Toward these goals, we are currently asking two questions: 1) What are the functions of imprinted non-coding RNAs in neurons? 2) What molecular mechanisms control parent-specific gene expression in neurons?
1) What are the functions of imprinted non-coding RNAs in neurons?
For our cells to function, our DNA must be turned into molecules capable of action. Certain genes produce RNAs which will serve as the template to make proteins (i.e., protein-coding mRNAs). Other genes produce non-coding RNAs which are regulatory molecules that determine when, where, and how proteins get created. Non-coding RNAs are found in many imprinted regions. Some imprinted long non-coding RNAs play essential roles in establishing or maintaining imprinted expression, but others have no known function. We previously generated a novel therapy for Angelman syndrome by targeting an imprinted non-coding RNA in the brain. This work spawned several active pre-clinical and clinical programs. We now seek to further reveal the roles of imprinted non-coding RNAs in the brain, including small non-coding RNAs, perhaps opening additional routes for treatment of imprinted disorders. Our findings will have broad implications for understanding a) how non-coding RNAs shape the output of our DNA and b) how non-coding RNAs modulate neurophysiological processes in health and disease.
2) What molecular mechanisms control parent-specific gene expression in neurons?
Each chromosome is one long string of DNA letters that is folded in three-dimensional space. The folding is carefully orchestrated such that some genetic elements, like promoters and enhancers, located far away in linear space are brought into close proximity. Therefore, changes in the way a chromosome is folded can create or disrupt interactions and impact gene expression. Recent technological advances enabled chromosome conformation to be captured in different cells of the body and have highlighted the dynamic roles of 3D genome organization in development. We are interested in determining how the 3D folding of the two parental genomes in offspring may dictate gene expression that is biased toward one parental copy (i.e. imprinted expression). We seek to understand the cause and consequence of DNA contacts that differ between the two sets of parental chromosomes. While our studies focus on discovering differences between maternally and paternally inherited chromosomes, we expect to uncover principles of chromosome conformation that widely apply to gene control in many cell types, tissues, and organisms.
Whipple AJ, Breton-Provencher V, Jacobs HN, Chitta U, Sur M, & Sharp PA. (2020) Imprinted maternally- expressed microRNAs antagonize paternally-driven gene programs in neurons. Mol Cell, 78:85-95.