The Gabel laboratory studies molecular mechanisms of gene regulation that contribute to development and plasticity in the mammalian brain. The lab combines 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. The lab has 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. Laboratory 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. The lab is 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.
- Smith AM, LaValle TA, Shinawi M, Ramakrishnan SM, Abel HJ, Hill CA, Kirkland NM, Rettig MP, Helton NM, Heath SE, Ferraro F, Chen DY, Adak S, Semenkovich CF, Christian DL, Martin JR, Gabel HW, Miller CA, Ley TJ. Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome. Nat Commun. Jul 27, 2021; 12(1):4549. doi: 10.1038/s41467-021-24800-7.
- Christian DL*, Wu DY*, Martin JR, Moore JR, Liu YR, Clemens AW, Nettles SA, Kirkland NM, Papouin T, Hill CA, Wozniak DF, Dougherty JD, Gabel HW. DNMT3A haploinsufficiency results in behavioral deficits and global epigenomic dysregulation shared across neurodevelopmental disorders. Cell Rep. Nov 24, 2020; 33(8):108416. doi: 10.1016/j.celrep.2020.108416.
- Clemens AW, Gabel HW. Emerging insights into the distinctive neuronal methylome. Trends Genet. Nov 2020; 36(11):816-832. doi: 10.1016/j.tig.2020.07.009. Epub 2020 Aug 21.
- Goodman JV, Yamada T, Yang Y, Kong L, Wu DY, Zhao G, Gabel HW, Bonni A. The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain. Nat Commun. Jul 9, 2020; 11(1):3419. doi: 10.1038/s41467-020-17065-z.
- Clemens AW*, Wu DY*, Moore JR, Christian DC, Zhao G, Gabel HW. MeCP2 represses enhancers through chromosome topology-associated DNA methylation. Molecular Cell. Epub Nov 26, 2019.
- Kinde, BZ, Wu D, Greenberg ME, Gabel HW. DNA methylation in the gene body influences MeCP2-mediated gene repression. PNAS. 2016; 113(52):15114-9. Epub 2016/12/15. doi: 10.1073/pnas.1618737114.
- Gabel HW, Kinde BZ, Stroud H, Harmin DA, Hemberg M, Gilbert CS, Ebert DH, Greenberg ME. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature. Jun 4, 2015; 522(7554):89-93. doi: 10.1038/nature14319. Epub 2015 Mar 11.
- Kinde BZ, Gabel HW, Gilbert CS, Griffith EC, Greenberg ME. Reading the unique DNA methylation landscape of the brain: Non-CpG methylation, hydroxymethylation, and MeCP2. PNAS. Jun 2, 2015; 112(22):6800-6. doi: 10.1073/pnas.1411269112. Epub Mar 4, 2015.
- 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. Oct 6, 2011; 72(1):72-85.
- Gabel HW, Ruvkun G. The exonuclease ERI-1 has a conserved dual role in 5.8S rRNA processing and RNAi. Nat Struc Mol Bio. May 2008; 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. May 20, 2005; 308(5725):1164-7.
See a complete list of Dr. Gabel’s publications on PubMed.
2002-2009, PhD in Genetics, Massachusetts General Hospital, Department of Molecular Biology, Harvard Medical School, Biological and Biomedical Sciences program. Dissertation advisor: Dr. Gary B. Ruvkun
1997-2001, AB Princeton University, Molecular Biology
2013-2014, William Randolph Hearst Research Fund Recipient
2010-2013, Damon Runyon Cancer Research Foundation Fellow
2016 Young Investigator, Mathers Foundation
2017 NARSAD Young Investigator, Brain and Behavior Research Foundation
2017 Klingenstein-Simons Fellowship in the Neurosciences