|Assistant Professor of Ophthalmology|
Johns Hopkins University School of Medicine
The Smith Building, Room 3041
400 North Broadway
Baltimore, MD 21287
Dr. Esumi is currently Assistant Professor of Ophthalmology at the Wilmer Eye Institute. She started her career as a pediatric oncologist in Japan. While she found treating children with cancer enormously rewarding, she became increasingly aware of the importance of basic research to understand disease better and treat patients more effectively. This experience ultimately led to her decision to study basic science in the US. After working in the field of cancer biology, Dr. Esumi decided to become a molecular biologist in eye research, with focus on gene regulation in the retinal pigment epithelium (RPE) (see Research Interest below).
Professional Training and Employment:
- Junior Resident in Pediatrics, Kyoto Prefectural University of Medicine, Japan
- Medical Staff in Pediatrics, Akashi City Hospital, Japan
- Senior Resident in Pediatrics, Kyoto Prefectural University of Medicine, Japan
- Postdoctoral Fellow, University of Texas M.D. Anderson Cancer Center, USA
- Visiting Associate, National Eye Institute (NEI)/NIH, USA
- Research Associate, Wilmer Eye Institute, Johns Hopkins University School of Medicine
- Instructor, Wilmer Eye Institute, Johns Hopkins University School of Medicine
- Assistant Professor, Wilmer Eye Institute, Johns Hopkins University School of Medicine
My long-term research interest is to elucidate the molecular mechanisms and networks that underlie RPE-specific gene expression. The RPE has many critical functions for supporting and nourishing retinal photoreceptors, and therefore is indispensable for vision. Mutations in a growing number of genes that are specifically or preferentially expressed in the RPE, such as RPE65, RLBP1, TIMP3, and BEST1 (formerly VMD2), can cause a variety of human retinal dystrophies. Of particular interest, abnormalities in the RPE, and in RPE gene regulation, have also been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in elderly Americans. Despite such important roles of the RPE, however, the information related to the molecular mechanisms controlling gene expression in the RPE is still very limited. To fill such knowledge gaps and advance our understanding of RPE physiology in general, our current and future research projects focus on the following areas.
1) Elucidate the molecular mechanisms regulating BEST1 expression in the RPE.
As a model system for studying RPE gene regulation, I chose human BEST1, the gene causing vitelliform macular dystrophy (Best disease) when mutated, because of its high and preferential expression in the RPE and its association to human retinal dystrophy. We demonstrated that the BEST1 -154 to +38 bp region is sufficient to direct RPE-specific expression in transgenic mice, and identified MITF and OTX2 as a regulator of BEST1 expression (JBC 2004, JBC 2007, and HMG 2009). My lab continues and expands the studies of RPE gene regulation using BEST1 as a model. We will further define regulatory DNA elements, identifying protein factors that bind to them, and elucidating their molecular interactions and posttranscriptional modifications through signal transduction pathways that change protein functions.
2) Define the network of transcription factors involved in RPE gene regulation.
Transcriptional control is regulated by multiple factors at multiple levels. As the first step to understand such a complex network controlling gene expression in the RPE, we aim to identify direct binding targets of transcription factors involved in RPE gene regulation, including MITF, OTX2, and possibly other factors identified in the future. We will use a genome-wide approach, chromatin immunoprecipitation (ChIP) combined with the next-generation sequencing technologies (ChIP-Seq). Identified binding locations will be validated and further studied to understand the regulatory network in the RPE.
3) Analyze how chromatin structure influences BEST1 transcription.
There is increasing evidence showing that chromatin structure is also a major player in the regulation of gene expression, and such epigenetic regulation has recently become the area of intense interest. My lab has begun and will expand studies designed to explore the role of chromatin in modulating RPE gene expression. We are using DNase I HS assay to analyze chromatin structure for finding active regulatory regions at the genomic locus around BEST1 in the RPE. We are also analyzing histone modification patterns of the BEST1 genomic locus in bovine RPE cells by ChIP with antibodies against various histone modifications. Furthermore, we will define how and which sequence-specific DNA-binding factors recruit proteins and/or complexes for modifying chromatin at the BEST1 genomic locus in the RPE.
4) Define functional roles of HTRA1 promoter polymorphisms implicated in AMD.
Multiple single nucleotide polymorphisms (SNPs) have been found in the upstream region of HTRA1 on chromosome 10q26, which was identified by linkage studies as one the regions that likely contain susceptibility genes for AMD. However, the critical region on 10q26 has been controversial, and the biological effects of these SNPs have not been clarified. We aim at testing functional effects of these SNPs in the HTRA1 promoter region along with detailed analysis of the HTRA1 promoter itself, and thereby helping resolve the controversy and also gain insights into the pathogenesis of AMD.
Relevant Recent Publications:
1. Masuda T, Esumi N†. SOX9, through interaction with MITF and OTX2, regulates BEST1
expression in the retinal pigment epithelium. 2010 (submitted)
2. Esumi N†, Kachi S, Hackler L Jr, Masuda T, Yang Z, Campochiaro PA, Zack DJ. BEST1
expression in the retinal pigment epithelium is modulated by OTX family members.
Hum Mol Genet 18 (1):128-141, 2009. (PMC2605189)
3. Le Y-Z, Zheng W, Rao P-C, Robert E. Anderson RE, Esumi N, Zack DJ, Zhu M. Inducible
expression of Cre recombinase in the retinal pigmented epithelium. Investig Ophthalmol
Vis Sci 49:1248-1253, 2008.
4. Esumi N†, Kachi S, Campochiaro PA, Zack DJ. VMD2 promoter requires two proximal E-box
sites for its activity in vivo and is regulated by the MITF-TFE family. J Biol Chem 282:1838-
5. Kachi S*, Esumi N*, Zack DJ, Campochiaro PA. Sustained expression after nonviral ocular
gene transfer using mammalian promoters. Gene There 13:798-804, 2006. * Equal contribution
6. Qian J, Esumi N, Chen Y, Wang Q, Chowers I, Zack DJ. Identification of regulatory targets
of tissue-specific transcription factors: application to retina-specific gene regulation.
Nucleic Acids Res 33:3479-3491, 2005.
7. Kachi S, Oshima Y, Esumi N, Kachi M, Rogers B, Zack DJ, Campochiaro PA. Nonviral
ocular gene transfer. Gene There 12:843-851, 2005.
8. Wang QL, Chen S, Esumi N, Swain PK, Haines HS, Peng G, Melia BM, McIntosh I,
Heckenlively JR, Jacobson SG, Stone EM, Swaroop A, Zack DJ. QRX, a novel homeobox
gene, modulates photoreceptor gene expression. Hum Mol Genet 13:1025-1040, 2004.
9. Esumi N†, Oshima Y, Li Y, Campochiaro PA, Zack DJ. Analysis of the VMD2 promoter and
implication of E-box binding factors in its regulation. J Biol Chem 279:19064-19073, 2004.