David Segal

image of David Segal

Professor

Departments

Biochemistry and Molecular Medicine
Pharmacology - Medicine
MIND Institute - UCD Medical Center
UC Davis Genome Center

Offices and Labs

4512 GBSF
754-9134

Profile Introduction

Zinc finger, TALE, CRISPR/Cas genome engineering and targeted gene regulation for applications in research and therapeutics, especially neurologic disorders.

Degrees

1996 PhD Biochemistry Univeristy of Utah
1989 BS Biology Cornell University

Research Interests

Genome and Epigenome Editing for the Study and Treatment of Disease

Almost every disease has a genetic component. Often this information is used only to determine how condemned a person is to develop disease. We would like to use the genetic information to fix the disease. A guiding principle for our work has been to study how nature does what it does, then attempt to use that knowledge to make useful tools to improve public health, either through increased knowledge or therapeutic intervention. Specific research foci in the Segal Lab revolve around engineering zinc finger, TALE, and CRISPR/Cas nucleases and transcription factors.

  • Manipulating epigenetic mechanisms in neurologic genetic diseases
    Angelman syndromes is a rare neurogenetic disease that is the textbook examples of imprinting disorder. We are using artificial transcription factors to activate the epigenetically silenced gene in in the brain. This project is funded by the Foundation for Angelman Syndrome Therapeutics..
  • Functional genomics of non-coding elements
    In collaboration with Peggy Farnham and the ENCODE consortium, we are using targetable nucleases and transcription factors based on zinc fingers, Transcription Activator-like Effector (TALE), and Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein (CRISPR/Cas) to disrupt non-coding genetic elements in the human genome to better understand their function. Our most recent efforts focus on creating epigenomic editing tools that can precisely manipulate epigenetic information at specific loci. Such tools can be used for the long-term control of gene expression for both research and therapeutic applications. 
  • Genetic variation in health and disease
    Several genetic variations (SNPs) have been associated with an increased risk of common complex disorders, such as colorectal cancer. In collaboration with Luis Carvajal-Carmona, we are using targetable nucleases identify causative SNPs and determine their mechanism of function. Our most recent efforts focus on creating tools that can precisely alter a single base pair at specific loci. Our approach overcomes the historic barrier of trying to study the affects of specific human mutations in a background of millions of other genetic differences between two individuals. 
  • High-throughput investigations of CRISPR-DNA interactions
    We continue to develop new methodologies for genome editing, such as methods to study off-target activity of CRISPRs and factors for targeted epigenetic modification. We employ methods of directed evolution for protein engineering and ChIP-seq and RNA-seq to examine the effects of tools on a genome-wide scale.

Zinc finger, TALE, CRISPR/Cas genome engineering and targeted gene regulation for applications in research and therapeutics, especially neurologic disorders.

Awards

2011 W.M. Keck Foundation Medical Research Award

Department and Center Affiliations

UC Davis Genome Center
UC Davis Cancer Center

ProfessionalSocieties

American Society for Gene and Cell Therapy
American Society of Human Genetics

CBS Grad Group Affiliations

Biochemistry, Molecular, Cellular and Developmental Biology
Integrated Genetics and Genomics

Specialties / Focus

Integrated Genetics and Genomics
  • Chromosome Biology
  • Human Genetics and Genomics
Biochemistry, Molecular, Cellular and Developmental Biology
  • Molecular Medicine
  • Chromosome Dynamics and Nuclear Function
  • Genomics, Proteomics and Metabolomics

Graduate Groups not Housed in CBS

Pharmacology and Toxicology

Labs

4617A GBSF website
  • Dr. Henny O'Geen (Project Scientist)
  • Ben Pyles (SRA III)
  • Dr. Ulrika Beitmere (Post-doc)
  • Dr. Antonio Gomez (Post-doc)
  • Nicole Coggins (MCIP)
  • Jesse Lopez (IGG)
  • Peter Deng (PTX)

Courses

• FRS 001 Fresh Sem: Gene Therapy - How Genes Control You and How You Can Controll Them (Fall)
• GGG 201A Advanced Genetic Analysis (Fall)
• BCB 211 Macromolecular Structure & Interactions (Fall)

Publications

1/8/2018 10:15:00 AM
  • Coggins, N.B., Stultz, J., O’Geen, H, Carvajal-Carmona, L.G., Segal, D.J. (2017) Methods for Scarless, Selection-Free Generation of Human Cells and Allele-Specific Functional Analysis of Disease-Associated SNPs and Variants of Uncertain Significance. Sci Rep. 7:15044.

  • O'Geen H, Ren C, Nicolet CM, Perez AA, Halmai J, Le VM, Mackay JP, Farnham PJ, Segal DJ. (2017) dCas9-based epigenome editing suggests acquisition of histone methylation is not sufficient for target gene repression. Nucleic acids research 45(17):9901-9916.
  • Lopez SJ, Dunaway K, Islam MS, Mordaunt C, Ciernia AV, Meguro-Horike M, Horike SI, Segal DJ, LaSalle J. (2017) UBE3A-mediated regulation of imprinted genes and epigenome-wide marks in human neurons. Epigenetics :0.
  • Bailus BJ, Pyles B, McAlister MM, O'Geen H, Lockwood SH, Adams AN, Nguyen JT, Yu A, Berman RF, Segal DJ. (2016) Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain. Molecular therapy : the journal of the American Society of Gene Therapy 24(3):548-55.
  • Fink KD, Deng P, Gutierrez J, Anderson JS, Torrest A, Komarla A, Kalomoiris S, Cary W, Anderson JD, Gruenloh W, Duffy A, Tempkin T, Annett G, Wheelock V, Segal DJ, Nolta JA. (2016) Allele-Specific Reduction of the Mutant Huntingtin Allele Using Transcription Activator-Like Effectors in Human Huntington's Disease Fibroblasts. Cell transplantation 25(4):677-86.
  • Tak YG, Hung Y, Yao L, Grimmer MR, Do A, Bhakta MS, O'Geen H, Segal DJ, Farnham PJ. (2016) Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. Nucleic acids research 44(9):4123-33.
  • O’Geen, H., Yu, A.S., and Segal, D.J. How specific is CRISPR/Cas9 really? (2015) Current Opinions in Chemical Biology. 29:72–78.

  • O'Geen, H., Henry, I.M., Bhakta, M.S., Meckler, J.F., Segal, D.J. (2015) A genome-wide analysis of Cas9 binding specificity using ChIP-seq and targeted sequence capture. Nucleic Acids Res. 43:3389-3404.

  • Bailus, B.J., Segal, D.J. (2014) The Prospect of Molecular Therapy for Angelman Syndrome and Other Autism Spectrum Disorders. BMC Neurosci, 15:76.

  • Lockwood, S.H., Guan, A., Yu, A.S., Zhang, C., Zykovich, A., Korf, I., Rannala, B., Segal, D.J. (2014) The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors. G3, pii: g3.114.012195.

  • Barrilleaux, B., Burow, D., Lockwood, S., Yu, A., Segal, D.J., Knoepfler, P. (2014) Miz-1 activates gene expression via a novel consensus DNA binding motif. PLoS One. 9:e101151.

  • Johnson, L.M., Du, J., Hale, C.J., Bischof, S, Feng, S., Chodavarapu, R.K., Zhong, X., Marson, G., Pellegrini, M., Segal, D.J., Patel, D.J., Jacobsen, S.E. (2014) SRA/SET domain-containing proteins link RNA polymerase V occupancy to DNA methylation. Nature, 507:124-128.

  • Bailus, B.J., Segal, D.J. (2014) The Prospect of Molecular Therapy for Angelman Syndrome and Other Autism Spectrum Disorders. BMC Neurosci, 15:76.

  • Lockwood, S.H., Guan, A., Yu, A.S., Zhang, C., Zykovich, A., Korf, I., Rannala, B., Segal, D.J. (2014) The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors. G3, pii: g3.114.012195.

  • Segal, D.J. and Meckler, J.F., (2013) Genome Engineering at the Dawn of the Golden Age, Annu. Rev. Genomics Hum. Genet, 14:135–158.
  • Meckler, J.F., Bhakta, M.S., Kim, M-S., Ovadia, R., Habrian, C.H., Zykovich, A., Yu, A., Lockwood, S.H., Morbitzer, R., Elsäesser, J., Lahaye, T., Segal, D.J., and Baldwin, E.P. (2013) Quantitative Analysis of TALE-DNA Interactions Suggests Polarity Effects, Nucleic Acids Res, 41:4118-4128.
  • Bhakta, M.S., Henry, I.M., Ousterout, D.G., Theva Das, K., Lockwood, S.H., Meckler, J.F., Wallen, M.C., Zykovich, As, Yu, Y., Leo, H., Xu, L., Gersbach, C.A. and Segal, D.J. (2013) Highly Active Zinc-Finger Nucleases by Extended Modular Assembly, Genome Research, 23:530-538.
  • Owens, J.B., Mauro, D., Stoytchev, I., Bhakta, M.S., Kim, M.-S., Segal, D.J. and Moisyadi, S. (2013) Transcription activator like effector (TALE) directed piggyBac transposition in human cells. Nucleic Acids Res, 41:9197-9207.

  • Meier, J.L., Yu, A., Korf, I., Segal, D.J. and Dervan, P.B. (2012) Guiding the Design of Synthetic DNA-Binding Molecules with Massively Parallel Sequencing, J Am Chem Soc. 134:17814-17822.
  • Zykovich, A., Korf, I. and Segal, D.J. (2009) Bind-n-Seq: high-throughput analysis of in vitro protein-DNA interactions using massively parallel sequencing. Nucleic Acids Res. 37:e151.
  • Kim, M.-S., Stybayeva, G., Lee, J.Y., Revzin, A., and Segal, D.J. (2011) A zinc finger protein array for the visual detection of pathogen-specific DNA sequences. Nucleic Acids Res. 39:e29.
  • Shimizu, Y., Şöllü, C., Meckler, J. M., Adriaenssens, A., Zykovich, A., Cathomen, T., and Segal, D.J. (2011) Adding Fingers To An Engineered Zinc Finger Nuclease Can Reduce Activity. Biochemistry, 50:5033-5041
  • Mackay, J.P., Font, J., and Segal, D.J. (2011) The prospects for designer single-stranded RNA-binding proteins. Nature Struct Mol Biol, 18:256-261
  • Furman, J. L., Badran, A. H., Ajulo, O., Porter, J. R., Stains, C. I., Segal, D. J., and Ghosh, I. (2010) Toward a General Approach for RNA-Templated Hierarchical Assembly of Split-Proteins, J Am Chem Soc. 132:11692-11701.
  • Szczepek, M., Brondani, V., Büchel, J., Serrano, L., Segal, D.J. and Cathomen, T. (2007) Structure-based redesign of the dimerization interface reduces the toxicity of zinc finger nucleases. Nat. Biotechnol., 25:786-793.
  • Alwin, S., Gere, M. B., Guhl, E., Effertz, K., Barbas, C. F., 3rd, Segal, D. J., Weitzman, M. D., and Cathomen, T. (2005). Custom Zinc-Finger Nucleases for Use in Human Cells. Mol Ther.
  • Carroll, D., Morton, J.J., Beumer, K.J. & Segal, D.J. (2006) Construction and Testing of Zinc Finger Nucleases. Nat. Protocols, 1:1329-1341.