Erin Clark, PhD
Postdoctoral Research Fellow
Nelson Lab
Brandeis University
(September 26, 2019)
Poised genes in the adult mouse brain
Any changes to gene expression (how the genetic information is read and used) can lead to dysfunction in the nervous system. Understanding why this happens could assist in finding new treatments and interventions. Dr. Clark is exploring the role of genes that have paused in their expression and how this relates to function in different neuron cell types.
The CNS contains a larger diversity of cell types than any other tissue in the body. This cellular diversity is critical for nervous system function and disruptions or disease often affect specific cell types. Cellular diversity is generated through complex regulatory networks that influence gene expression most of which are established during development and refined by postnatal input from the environment. Once established, the cell types underlying higher-order properties that contribute to cognitive function and dysfunction depend on continued and precise regulation of gene expression, which is largely governed by DNA regulatory elements such as enhancers and the protein regulators that bind to them. A better understanding of the regulatory logic that governs cell type specific gene expression in the brain would facilitate more precise genetic tools and clinical interventions.
To study cell type specific gene regulation we have collected high quality ATAC- and RNA-seq profiles from 16 neuronal cell types from across the mouse brain. We find that a surprising fraction of differentially expressed genes lack a correlated pattern of differential chromatin accessibility at the transcription start site (TSS). These genes have an open TSS but lack RNA expression. We find many thousands of genes in this Open-Off state, which produce small RNAs from the 5’ end suggesting loaded but paused RNA polymerase. These paused genes contain significant information distinguishing neuronal cell types. Most of these genes are expressed or closed (not paused) in at least one other neuronal type. This diversity of TSS-expression state suggests developmental trajectories differentially influence chromatin and expression status, and a gene that is paused in one cell type is often expressed and possibly involved in basal cellular function in another. Interestingly, genetic knock-out of the layer-specific transcription factor RORγ induces Layer 4 neurons to take on a Layer 5-like identity in terms of gene expression and induces several hundred genes to transition from Closed-Off to paused (Open-Off).
I am currently exploring how these paused genes might contribute to neuronal function, when during development they become paused, and the mechanisms involved in regulating their expression across cell types.