Simon Gregory

Overview:

My principal area of research involves elucidating the molecular mechanisms underlying multi-factorial diseases. My lab is primarily interested identifying the complex genetic factors that give rise to multiple sclerosis, autism and cardiovascular disease. We are using targeted approaches to identify differential methylation of the oxytocin receptor gene (OXTR) in individuals with autism, and applying these data to an NICHD funded ACE award, SOARS-B, to assess long term use of oxytocin nasal spray to improve social reciprocity in 300 children with autism, and for which we are developing e/genetic and transcriptomic predictors of response and effects of long term drug exposure. My MS laboratories at Duke University and the David H Murdock Research Institute (DHMRI) are using cell signaling and immune cell flow sorting to establish the role of IL7R signaling in the development of MS; we have developed three novel mouse strains to induce EAE susceptibility and to investigate allele and splicing specific effects of IL7R in these novel MS models; I am PI of the MURDOCK-MS collection, a cross sectional MS cohort of ~1000 MS patients that will provide the basis for genetic, genomic and metabolomic biomarker identification of MS disease development and progression. I am also Director of the nascent Duke Center for Research in Autoimmunity and MS within the Duke Department of Neurology.

Positions:

Professor in Neurology

Neurology, MS & Neuroimmunology
School of Medicine

Research Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of Duke Molecular Physiology Institute

Duke Molecular Physiology Institute
School of Medicine

Education:

B.A.Sc. 1990

RMIT University (Australia)

Ph.D. 2003

Open University, Milton Keynes (U.K.)

Grants:

High-Resolution CGH Characterization of Brain Tumors

Administered By
Duke Molecular Physiology Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Linkage and candidate gene analysis in non-syndromic Chiari type I

Administered By
Duke Molecular Physiology Institute
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Social Relationship Qualities as Predictors of Health & Aging from Adolescence thru Midlife

Administered By
Psychology and Neuroscience
Role
Co Investigator
Start Date
End Date

Characterizing the (epi)genetics of oxytocin response in clinical and animal models

Administered By
Duke Molecular Physiology Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Specific and Pervasive Symptoms in Adults with Multiple Sclerosis Using the MURDOCK-MS Dataset: A Secondary Analysis

Administered By
School of Nursing
Awarded By
National Institutes of Health
Role
Significant Contributor
Start Date
End Date

Publications:

Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma.

Fibrolamellar carcinoma (FLC) is characterized by in-frame fusion of DnaJ heat shock protein family (Hsp40) member B1 (DNAJB1) with protein kinase cAMP-activated catalytic subunit α (PRKACA) and by dense desmoplasia. Surgery is the only effective treatment because mechanisms supporting tumor survival are unknown. We used single-cell RNA sequencing to characterize a patient-derived FLC xenograft model and identify therapeutic targets. Human FLC cells segregated into four discrete clusters that all expressed the oncogene Yes-associated protein 1 (YAP1). The two communities most enriched with cells coexpressing FLC markers [CD68, A-kinase anchoring protein 12 (AKAP12), cytokeratin 7, epithelial cell adhesion molecule (EPCAM), and carbamoyl palmitate synthase-1] also had the most cells expressing YAP1 and its proproliferative target genes (AREG and CCND1), suggesting these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, indicating these were fibrogenic FLC cells. All clusters expressed the YAP1 target gene and mesothelial progenitor marker mesothelin, and many mesothelin-positive cells coexpressed albumin. Trajectory analysis predicted that the four FLC communities were derived from a single cell type transitioning among phenotypic states. After establishing a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, YAP1 was inhibited, which significantly reduced expression of known YAP1 target genes as well as cell growth and migration. Thus, both FLC epithelial and stromal cells appear to arise from DNAJB1-PRKACA fusion in a YAP1-dependent liver mesothelial progenitor, identifying YAP1 as a target for FLC therapy.
Authors
Jewell, ML; Gibson, JR; Guy, CD; Hyun, J; Du, K; Oh, S-H; Premont, RT; Hsu, DS; Ribar, T; Gregory, SG; Diehl, AME
MLA Citation
Jewell, Mark L., et al. “Single-Cell RNA Sequencing Identifies Yes-Associated Protein 1-Dependent Hepatic Mesothelial Progenitors in Fibrolamellar Carcinoma..” Am J Pathol, vol. 190, no. 1, Jan. 2020, pp. 93–107. Pubmed, doi:10.1016/j.ajpath.2019.09.018.
URI
https://scholars.duke.edu/individual/pub1418037
PMID
31669305
Source
pubmed
Published In
The American Journal of Pathology
Volume
190
Published Date
Start Page
93
End Page
107
DOI
10.1016/j.ajpath.2019.09.018

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer.

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.
Authors
Gupta, S; Hovelson, DH; Kemeny, G; Halabi, S; Foo, W-C; Anand, M; Somarelli, JA; Tomlins, SA; Antonarakis, ES; Luo, J; Dittamore, RV; George, DJ; Rothwell, C; Nanus, DM; Armstrong, AJ; Gregory, SG
URI
https://scholars.duke.edu/individual/pub1421556
PMID
31705765
Source
pubmed
Published In
Genes Chromosomes Cancer
Published Date
DOI
10.1002/gcc.22824

Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1).

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome-wide association study (EWAS) for all-cause mortality with whole-transcriptome data in a cardiovascular cohort (CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow-up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δβ). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated (P<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate-adjusted P<0.10: cg08215811 (SLC4A9; log2 fold change=-0.14); cg17845532 (MATK; fold change=-0.26); and cg17944110 (castor zinc finger 1 [CASZ1]; FC=0.26; P<0.0001; false discovery rate-adjusted P=0.046-0.080). Meta-analysis identified 6 probes (false discovery rate-adjusted P<0.05): the 3 above, cg20428720 (intergenic), cg17647904 (NCOR2), and cg23198793 (CAPN3). Messenger RNA expression of 2 MATK isoforms was lower in cases (fold change=-0.24 [P=0.007] and fold change=-0.61 [P=0.009]). The CASZ1, NCOR2, and CAPN3 transcripts did not show differential expression (P>0.05); the SLC4A9 transcript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element, UBIAD1 (P=0.01) and CLSTN1 (P=0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all-cause mortality. Methylation in CASZ1 may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.
Authors
Abdulrahim, JW; Kwee, LC; Grass, E; Siegler, IC; Williams, R; Karra, R; Kraus, WE; Gregory, SG; Shah, SH
MLA Citation
Abdulrahim, Jawan W., et al. “Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1)..” J Am Heart Assoc, vol. 8, no. 21, Nov. 2019. Pubmed, doi:10.1161/JAHA.119.013228.
URI
https://scholars.duke.edu/individual/pub1416494
PMID
31642367
Source
pubmed
Published In
Journal of the American Heart Association
Volume
8
Published Date
Start Page
e013228
DOI
10.1161/JAHA.119.013228

Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome.

The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH2-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. P = 7.5 × 10-4) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. P = 1.6 × 10-6). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.
Authors
Kwee, LC; Neely, ML; Grass, E; Gregory, SG; Roe, MT; Ohman, EM; Fox, KAA; White, HD; Armstrong, PW; Bowsman, LM; Haas, JV; Duffin, KL; Chan, MY; Shah, SH
MLA Citation
Kwee, Lydia Coulter, et al. “Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome..” Physiol Genomics, vol. 51, no. 10, Oct. 2019, pp. 506–15. Pubmed, doi:10.1152/physiolgenomics.00033.2019.
URI
https://scholars.duke.edu/individual/pub1411828
PMID
31530226
Source
pubmed
Published In
Physiological Genomics
Volume
51
Published Date
Start Page
506
End Page
515
DOI
10.1152/physiolgenomics.00033.2019

Yap1 AS A THERAPEUTIC TARGET IN FIBROLAMELLAR CARCINOMA

Authors
Oh, S-H; Jewell, M; Premont, RT; Gibson, J; Glover, W; Gregory, SG; Hsu, D; Guy, CD; Diehl, AM
MLA Citation
Oh, Seh-Hoon, et al. “Yap1 AS A THERAPEUTIC TARGET IN FIBROLAMELLAR CARCINOMA.” Hepatology, vol. 70, WILEY, 2019, pp. 888A-889A.
URI
https://scholars.duke.edu/individual/pub1417037
Source
wos
Published In
Hepatology (Baltimore, Md.)
Volume
70
Published Date
Start Page
888A
End Page
889A