Harrison Gabel Research Abstract
Our laboratory studies molecular mechanisms of gene regulation that contribute to development and plasticity in the mammalian brain. We combine genetic, genomic, and biochemical approaches in mouse and human models to identify and dissect important gene-regulatory pathways in neurons. A broad goal of this work is to understand how disruption of transcriptional regulation can lead to neurodevelopmental disease, including autism spectrum disorders. Current areas of focus in the lab include:
The unique neuronal epigenome Recent evidence indicates that two forms of DNA methylation which are rare in most cell types, hydroxymethylation and non-CpG methylation, accumulate to high levels specifically in neurons. We have found that MeCP2, the methyl-DNA binding protein disrupted in the severe neurological disorder Rett syndrome, binds to non-CpG DNA methylation to regulate the expression of important neuronal genes. Using high-throughput sequencing approaches (e.g. ChIP-Seq, and Bisulfite-Seq), we are studying how distinctive DNA methylation patterns are established in neurons, and investigating how MeCP2 and other chromatin proteins regulate genes when bound to these unique methyl marks.
Expression of extremely long genes in the brain We have recently uncovered a surprising attribute of the neuronal transcriptome: Neurons express extremely long genes (e.g. >100kb) at much higher levels than non-neural cell types, which do not express these genes substantially. The longest genes in the genome tend to encode proteins that are critical for neural function (e.g. cell adhesion molecules, ion channels, and synaptic receptors), but the mechanisms that neurons use to efficiently transcribe and regulate these genes, which are up to one hundred times longer than average, are not well understood. Our studies have revealed that MeCP2 regulates extremely long genes, and suggest that disrupted expression of very long genes may contribute to pathology in Rett syndrome and other neurological diseases. We are now investigating how neurons express and regulate the longest genes in the genome, with an eye toward understanding how disruption of this process can lead to neurological dysfunction.