Stadtman Investigator:

Research interests: Regulation of cytokine loci and immune regulomes

Contact Information: 301-402-5909

10 Center Dr
Building 10, Room 5S261
Bethesda, Maryland 20892

Biography

Dr. Shih received her M.S. in Microbiology from National Taiwan University in 2006 and Ph.D. in Immunology from Duke University in 2012. As a graduate student, she worked in Dr. Michael Krangel’s lab studying the role of three-dimensional chromatin looping and the key looping factor, CTCF, in gene regulation during thymocyte development. In 2013, she joined John O’Shea’s lab in NIAMS where she began her work on lymphocyte regulomes as a postdoctoral fellow. She received a NIH K22 career development award in 2018 and was jointly appointed by NEI and NINDS as a Stadtman Tenure-track Investigator in 2019. Her research focuses on understanding the regulation of cytokine loci and immune regulomes in health and neurodegenerative diseases in eye and brain, with an ultimate goal of developing more specific and efficacious therapies.

Current research

The Neuro-Immune Regulome Unit (NIRU) aims to understand the mechanisms that precisely regulate gene expression in lymphoid cells through multidisciplinary genomic approaches. Lymphoid cells communicate the perturbation of homeostasis by production of cytokines, dysregulation of which results in neural and ocular inflammation in many disorders, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, uveitis, and age-related macular degeneration. Understanding the basic pathophysiology of cytokine production in these contexts – for example, their source and regulation – represents a promising path for the development of more specific and efficacious therapies.

Precise orchestration of gene regulation in lymphocytes is mediated by networks of signaling molecules, transcription factors, and genomic regulatory regions, which in sum is termed regulomes. Previously, we have identified lineage-specific regulomes in tissue-resident innate and adaptive lymphocytes in both homeostatic and activated states by integrating cutting-edge techniques and computational approaches (Shih et al., Cell, 2016; Harrison et al., Science, 2018; Kobayashi et al., Cell, 2019; Nagashima et al., Immunity, 2019). We now are focusing on two key biological questions 1) How do distinct stimuli regulate cytokines in a context-specific manner? 2) How cytokines contribute to the progression of neurodegeneration, such as Alzheimer’s disease and age-related macular degeneration? By analyzing lymphocyte regulomes with distinct genetic background in human and engineered mice, we aim to further our understanding of molecular mechanisms that contribute to aging and neurodegenerative diseases.

Selected publications

  1. Morrison TA, Hudson WH, Chisolm DA, Kanno Y, Shih HY, Ahmed R, Henao-Mejia J, Hafner M, O'Shea JJ. Evolving Views of Long Noncoding RNAs and Epigenomic Control of Lymphocyte State and Memory. Cold Spring Harb Perspect Biol.  2021. PMID: 34001528
  2. Fernando N, Sciumè G, O'Shea JJ, Shih HY. Multi-Dimensional Gene Regulation in Innate and Adaptive Lymphocytes: A View From Regulomes. Front Immunol. 2021. PMID: 33841440
  3. Wu W, Hill SE, Nathan WJ, Paiano J, Callen E, Wang D, Shinoda K, van Wietmarschen N, Colón-Mercado JM, Zong D, De Pace R, Shih HY, Coon S, Parsadanian M, Pavani R, Hanzlikova H, Park S, Jung SK, McHugh PJ, Canela A, Chen C, Casellas R, Caldecott KW, Ward ME, Nussenzweig A. Neuronal enhancers are hotspots for DNA single-strand break repair. Nature. 2021 PMID:33767446
  4. Mikami Y, Philips RL, Sciumè G, Petermann F, Meylan F, Nagashima H, Yao C, Davis FP, Brooks SR, Sun HW, Takahashi H, Poholek AC, Shih HY, Afzali B, Muljo SA, Hafner M, Kanno Y, O'Shea JJ. MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23. Immunity. 2021 PMID: 33657395
  5. Sciumè G, Mikami Y, Jankovic D, Nagashima H, Villarino AV, Morrison T, Yao C, Signorella S, Sun HW, Brooks SR, Fang D, Sartorelli V, Nakayamada S, Hirahara K, Zitti B, Davis FP, Kanno Y, O’Shea JJ, Shih HY. Rapid enhancer landscape remodeling and transcription factor repurposing enable high magnitude gene induction upon acute activation of NK cells. Immunity. 2020 PMID: 33010223
  6. Göschl L, Preglej T, Boucheron N, Saferding V, Müller L, Platzer A, Hirahara K, Shih HY, Backlund J, Matthias P, Niederreiter B, Hladik A, Kugler M, Gualdoni GA, Scheinecker C, Knapp S, Seiser C, Holmdahl R, Tillmann K, Plasenzotti R, Podesser B, Aletaha D, Smolen JS, Karonitsch T, Steiner G, Ellmeier W, Bonelli M. Histone deacetylase 1 (HDAC1): A key player of T cell-mediated arthritis. J Autoimmun. 2020 PMID: 31883829
  7. Petermann F, Pękowska A, Johnson CA, Jankovic D, Shih HY, Jiang K, Hudson WH, Brooks SR, Sun HW, Villarino AV, Yao C, Singleton K, Akondy RS, Kanno Y, Sher A, Casellas R, Ahmed R, O'Shea JJ. The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1. Mol Cell. 2019 PMID: 31377117
  8. Nagashima H, Mahlakõiv T, Shih HY, Davis FP, Meylan F, Huang Y, Harrison OJ, Yao C, Mikami Y, Urban JF Jr, Caron KM, Belkaid Y, Kanno Y, Artis D, O'Shea JJ. Neuropeptide CGRP Limits Group 2 Innate Lymphoid Cell Responses and Constrains Type 2 Inflammation. Immunity. 2019 PMID: 31353223 
  9. Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA, Shih HY, Heuston EF, Kirby M, Anderson S, Cheng J, Khan O, Handon R, Reilley J, Fioravanti J, Hu J, Gossa S, Wherry EJ, Gattinoni L, McGavern DB, O'Shea JJ, Schwartzberg PL, Wu T. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat Immunol. 2019 PMID: 31209400 
  10. Kobayashi T, Voisin B, Kim DY, Kennedy EA, Jo JH, Shih HY, Truong A, Doebel T, Sakamoto K, Cui CY, Schlessinger D, Moro K, Nakae S, Horiuchi K, Zhu J, Leonard WJ, Kong HH and Nagao K. Homeostatic control of sebaceous glands by innate lymphoid cells regulates commensal bacteria equilibrium. Cell. 2019 PMID: 30712873 
  11. Schwartz DM, Farley T, Richoz N, Yao C, Shih HY, Petermann F, ZhangY, SunHW, Hayes E, MikamiY, JiangK, DavisFP, KannoY, Milner JD, SiegelR, LaurenceA, MeylanF, O’Shea JJ. Retinoic acid receptor alpha represses a Th9 transcriptional and epigenomic program. Immunity. 2019 PMID: 30650370
  12. Harrison OJ, Linehan JL, Shih HY, Bouladoux N, Han SJ, Smelkinson M, Sen SK, Byrd AL, Enamorado M, Yao C, Tamoutounour S, Laethem FV, Hurabielle C, Collins N, Paun A, Salcedo R, O’Shea JJ, Belkaid Y. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science. 2018 PMID: 30523076
  13. Povoleri G, Nova-Lamperti E, Scottà C, Fanelli G, Chen YC, Becker PD, Boardman D, Costantini B, Romano M, Pavlidis P, McGregor R, Pantazi E, Chauss D, Sun HW, Shih HY, Cousins DJ, Cooper N, Powell N, Kemper C, Pirooznia M, Laurence A, Shahram Kordasti S, Kazemian M, Lombardi G, Afzali B. Human retinoic acid–regulated CD161+regulatory T cells support wound repair in intestinal mucosa. Nat Immunol. 2018 PMID: 30397350
  14. Mikami Y, Scarno G, Zitti B, Shih HY, Kanno Y, Santoni A, O'Shea JJ, Sciumè G. NCR+ ILC3 maintain larger STAT4 reservoir via T-BET to regulate type 1 features upon IL-23 stimulation in mice. Eur J Immunol. 2018 PMID: 29524223
  15. Loguercio S, Barajas-Mora EM, Shih HY, Krangel MS, Feeney AJ. Variable extent of lineage-specificity and developmental stage-specificity of cohesin and CCCTC-binding factor binding within the immunoglobulin and T cell receptor loci. Front Immunol. 2018 PMID: 29593713
  16. Rahman MJ, Rodrigues KB, Quiel JA, Liu Y, Bhargava V, Zhao Y, Hotta-Iwamura C, Shih HY, Lau-Kilby AW, Malloy AM, Thoner TW, Tarbell KV. Restoration of the type I IFN-IL-1 balance through targeted blockade of PTGER4 inhibits autoimmunity in NOD mice. JCI Insight. 2018 PMID: 29415894
  17. Sciumè G, Shih HY, Mikami Y, O'Shea JJ. Epigenomic views of innate lymphoid cells. Front Immunol. 2017 PMID: 29250060
  18. Iwata S, Mikami Y, Sun HW, Brooks SR, Jankovic D, Hirahara K, Onodera A, Shih HY, Kawabe T, Jiang K, Nakayama T, Sher A, O'Shea JJ, Davis FP, Kanno Y. The transcription factor T-bet limits amplification of Type I IFN transcriptome and circuitry in T helper 1 cells. Immunity. 2017 PMID: 28623086
  19. Roychoudhuri R, Clever D, Li P, Wakabayashi Y, Quinn KM, Klebanoff CA, Ji Y, Sukumar M, Eil RL, Yu Z, Spolski R, Palmer DC, Pan JH, Patel SJ, Macallan DC, Fabozzi G, Shih HY, Kanno Y, Muto A, Zhu J, Gattinoni L, O'Shea JJ, Okkenhaug K, Igarashi K, Leonard WJ, Restifo NP. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat Immunol. 2016 PMID: 27158840 
  20. Shih HY*#, Sciumè G*, Mikami Y*, Guo L, Sun HW, Brooks S, Urban J, Davis F, Kanno Y, O’Shea JJ#. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell. 2016 PMID: 27156451 (recommended by F1000PRime and rated as “Exceptional”) *co-first authors #corresponding authors
  21. Villarino A, Laurence A, Robinson GW, Bonelli M, Dema B, Afzali B, Shih HY, Sun HW, Brooks SR, Hennighausen L, Kanno Y, O'Shea JJ. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. Elife. 2016 PMID: 26999798 
  22. Dell'Orso S, Wang AH, Shih HY, Saso K, Berghella L, Gutierrez-Cruz G, Ladurner AG, O'Shea JJ, Sartorelli V, Zare H. The Histone Variant macroH2A1.2 is necessary for the activation of muscle enhancers and recruitment of the transcription factor Pbx1. Cell Rep. 2016 PMID: 26832413
  23. Chen L, Carico Z, Shih HY, Krangel MS. A discrete chromatin loop in the mouse Tcra-Tcrd locus shapes the TCRδ and TCRα repertoires. Nat Immunol. 2015 PMID: 26258942
  24. Hirahara K, Onodera A, Villarino AV, Bonelli M, Sciumè G, Laurence A, Sun HW, Brooks SR, Vahedi G, Shih HY, Gutierrez-Cruz G, Iwata S, Suzuki R, Mikami Y, Okamoto Y, Nakayama T, Holland SM, Hunter CA, Kanno Y, O'Shea JJ. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity. 2015 PMID: 25992861
  25. Boudil A, Matei IR, Shih HY, Bogdanoski G, Yuan JS, Chang SG, Montpellier B, Kowalski PE, Voisin V, Bashir S, Bader GD, Krangel MS, Guidos CJ. IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection. Nat Immunol. 2015 PMID: 25729925
  26. Shih HY, Sciumè G, Poholek AC, Vahedi G, Hirahara K, Villarino AV, Bonelli M, Bosselut R, Kanno Y, Muljo SA, O'Shea JJ. Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunol Rev. 2014 PMID: 25123275
  27. Bonelli M, Shih HY, Hirahara K, Singelton K, Laurence A, Poholek A, Hand T, Mikami Y, Vahedi G, Kanno Y, O'Shea JJ. Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes. Curr Top Microbiol Immunol. 2014 PMID: 24831346
  28. Shih HY, Krangel MS. Chromatin architecture, CTCF and V(D)J recombination: managing long-distance relationships at antigen receptor loci. J Immunol. 2013 PMID: 23645930
  29. Shih HY, Verma-Gaur V, Feeney AJ, Galjart N, Krangel MS. T cell receptor alpha gene recombination is supported by a Tcra enhancer and CTCF-dependent chromatin hub. Proc Natl Acad Sci U S A. 2012 PMID: 23169622
  30. Kondilis-Mangum HD, Shih HY, Mahowald G, Sleckman BP, Krangel MS. Regulation of TCRb allelic exclusion by gene segment proximity and accessibility. J Immunol. 2011 PMID: 22079986 
  31. Ko TM, Chung WH, Wei CY, Shih HY, Chen JK, Lin CH, Chen YT, Hung SI. Shared and restricted T-cell receptor use is crucial for carbamazepine-induced Stevens-Johnson syndrome. J Allergy Clin Immunol. 2011 PMID: 21924464
  32. Shih HY, Hao B, Krangel MS. Orchestrating T-cell receptor a gene assembly through changes in chromatin structure and organization. Immunol Res. 2010 PMID: 21128009 
  33. Shih HY, Krangel MS. Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination. J Exp Med. 2010 PMID: 20696701
  34. Hung SI, Chung WH, Jee SH, Chen WC, Chang YT, Lee WR, Hu SL, Wu MT, Chen GS, Wong TW, Hsiao PF, Chen WH, Shih HY, Fang WH, Wei CY, Lou YH, Huang YL, Lin JJ, Chen YT. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006 PMID: 16538176
Last updated: July 7, 2021