Harrison W. Gabel, Ph.D.
Molecular Genetics and Genomics Program
Molecular Cell Biology Program
814 McDonnell Medical Science Building
Epigenetics, Neurodevelopment, Rett syndrome, non-CpG DNA methylation, Transcription, Autism Spectrum Disorder, Neurodevelopmental disease
Exploration of functions for neuron-specific regulators of gene expression, leveraging genes and mechanisms implicated in human neurologic disease to point us toward critical pathways in the brain.
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 continuing to investigate 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
Gabel H.W., Kinde B.Z., Stroud H., Harmin D.A., Hemberg M., Gilbert C.S., Ebert D.H., Greenberg M.E. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. 2015 Jun 4;522(7554):89-93. doi: 10.1038/nature14319. Epub 2015 Mar 11.
Kinde, B.Z., Gabel H.W., Gilbert C.S., Griffith E.C., Greenberg M.E. Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. PNAS. 2015 Jun 2;112(22):6800-6. doi: 10.1073/pnas.1411269112. Epub 2015 Mar 4.
Spiegel I., Mardinly A.R., Gabel H.W., Bazinet J.E., Couch C.H., Tzeng C.P., Harmin D.A., & Greenberg M.E. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell type-specific gene programs. Cell. 2014 May 22;157(5):1216-29. doi: 10.1016/j.cell.2014.03.058.
Ebert DH, Gabel HW, Robinson ND, Kastan NR, Hu LS, Navarro AJ, Lyst MJ, Ekiert R, Bird AP, and Greenberg ME. Activity-Dependent Phosphorylation of MeCP2 T308 Regulates Interaction with NCoR. Nature. 2013 Jul 18;499(7458):341-5. doi: 10.1038/nature12348
Cohen S, Gabel HW, Hemberg M, Hutchinson AN, Sadacca LA, Ebert DH, Harmin DA, Greenberg RS, Verdine VK, Zhou Z, Wetsel WC, West AE, Greenberg ME. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron. 2011 Oct 6;72(1):72-85.
Zhang C, Montgomery TA, Gabel HW, Fischer SE, Phillips CM, Fahlgren N, Sullivan CM, Carrington JC, Ruvkun G. mut-16 and other mutator class genes modulate 22G and 26G siRNA pathways in Caenorhabditis elegans. PNAS. 2011 Jan 25;108(4):1201-8. Epub 2011 Jan 18.
Gabel HW, Ruvkun G. The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi. Nat. Struc. Mol. Bio. 2008 May;15(5):531-3.
Kim JK, Gabel HW, Kamath RS, Tewari M, Pasquinelli A, Rual JF, Kennedy S, Dybbs M, Bertin N, Kaplan JM, Vidal M, Ruvkun G. Functional genomic analysis of RNA interference in C.elegans. Science. 2005 May 20;308(5725):1164-7.
Last Updated: 1/11/2016 2:30:26 PM