Harrison W. Gabel, Ph.D.

Associate Professor

Neurosciences Program
Molecular Genetics and Genomics Program
Molecular Cell Biology Program

  • 314-362-9814

  • 314-362-3446

  • 814 McDonnell Medical Science Building

  • gabelh@wustl.edu

  • 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.

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 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

Selected Publications:

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. 2015 Jun 4;522(7554):89-93. doi: 10.1038/nature14319. Epub 2015 Mar 11.

Kinde, BZ, Wu D, Greenberg ME, Gabel HW DNA methylation in the gene body influences MeCP2-mediated gene repression Proc Natl Acad Sci U S A. 2016 Dec 13. pii: 201618737. [Epub ahead of print]

Stroud H, Su SC, Hrvatin S, Greben AW, Renthal W, Boxer LD, Nagy MA, Hochbaum DR, Kinde B, Gabel HW, Greenberg ME. Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States. Cell. 2017 Oct 16. pii: S0092-8674(17)31141-8. doi: 10.1016/j.cell.2017.09.047. [Epub ahead of print]

McCoy MJ, Paul AJ, Victor MB, Richner M, Gabel HW, Gong H, Yoo AS, Ahn TH. LONGO: an R package for interactive gene length dependent analysis for neuronal identity. Bioinformatics. 2018 Jul 1;34(13):i422–i428, https://doi.org/10.1093/bioinformatics/bty243

Chen X, Chanda A, Ikeuchi Y, Zhang X, Goodman J, Reddy N, Majidi S, Wu D, Smith S, Godec A, Oldenborg A, Gabel H, Zhao G, Bonni S, Bonni A. The Transcriptional Regulator SnoN Promotes the Proliferation of Cerebellar Granule Neuron Precursors in the Postnatal Mouse Brain. J Neurosci. 2019 Jan 2;39(1):44-62. doi: 10.1523/JNEUROSCI.0688-18.2018. Epub 2018 Nov 13. PubMed PMID: 30425119

Schlosberg CE, Wu DY, Gabel HW, Edwards JR. ME-Class2 reveals context dependent regulatory roles for 5-hydroxymethylcytosine. Nucleic Acids Res. 2019 Mar 18;47(5):e28. doi: 10.1093/nar/gkz001.

Clemens AW*, Wu DY*, Moore JR, Christian DC, Zhao G, Gabel HW. MeCP2 represses enhancers through chromosome topology-associated DNA methylation. Molecular Cell. Epub 2019 Nov 26.

Kopp ND, Nygaard KR, Liu Y, McCullough KB, Maloney SE, Gabel HW, Dougherty JD. Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA binding and long-term behavioral consequences. Hum Mol Genet. 2020 Jun 3;29(9):1498-1519. doi: 10.1093/hmg/ddaa070.

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. 2020 Jul 9;11(1):3419. doi: 10.1038/s41467-020-17065-z.

Cates K, McCoy MJ, Kwon JS, Liu Y, Abernathy DG, Zhang B, Liu S, Gontarz P, Kim WK, Chen S, Kong W, Ho JN, Burbach KF, Gabel HW, Morris SA, Yoo AS. Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs. Cell Stem Cell. 2020 Sep 17;. doi: 10.1016/j.stem.2020.08.015. [Epub ahead of print]

Clemens AW, Gabel HW. Emerging Insights into the Distinctive Neuronal Methylome. Trends Genet. 2020 Nov;36(11):816-832. doi: 10.1016/j.tig.2020.07.009. Epub 2020 Aug 21.

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. 2020 Nov 24;33(8):108416. doi: 10.1016/j.celrep.2020.108416. PMID: 33238114

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. 2021 Jul 27;12(1):4549. doi: 10.1038/s41467-021-24800-7.

Chen J, Lambo ME, Ge Xia,Dearborn JT, Liu Y, McCullough KB, Swift RG, Tabachnick DR, Tian L, Noguchi K, Garbow JR, Constantino JN, Gabel HW, Hengen KB, Maloney SE, Dougherty JD. A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation. BioRxiv. doi: https://doi.org/10.1101/2020.12.17.423095

Reddy NC, Majidi SP, Kong L, Nemera M, Ferguson CJ, Moore, M, Gocalves TM, Liu H-K Fitzpatrick JAJ, Zhao G, Yamada T, Bonni A, Gabel HW. CHARGE Syndrome Protein CHD7 Regulates Epigenomic Activation of Enhancers in Granule Cell Precursors and Gyrification of the Cerebellum. In Press Nature Commun.

Last Updated: 9/30/2021 1:30:14 PM

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