Han-Yu Shih, Ph.D.

Headshot of Han-Yu Shih
Earl Stadtman Tenure-Track Investigator and NINDS Adjunct Investigator
Neuro-Immune Regulome Unit, NEI

BG 10 RM 5S261A

Dr. Shih received her B.S. and M.S. from National Taiwan University in 2006 and Ph.D. from Duke University in 2012. As a graduate student, she studied the role of chromatin looping and the transcription factor, CTCF, in gene regulation during thymocyte development. In 2013, she joined NIAMS at the NIH as a postdoctoral fellow to study innate lymphoid cell regulomes in homeostasis and infectious diseases using genomic and computational approaches. 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 current research focuses on deciphering transcriptomic and epigenomic regulation of lymphocytes in aging and neurodegenerative diseases in CNS, with an ultimate goal of developing more specific and efficacious therapies.

Neuro-Immune Regulome Unit Website

Our research 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.

Nilisha Elizabeth Fernando, Ph.D. Postdoctoral Fellow  nilisha.fernando@nih.gov 301-402-5909 
Chunhong Liu, Ph.D. Senior Scientist  chunhong.liu@nih.gov 301-435-3024 
William F. Montgomery, B.A. Postbaccalaureate IRTA  will.montgomery@nih.gov 301-496-2612 
Lauren N. Reich, B.S. Postbaccalaureate IRTA  lauren.reich@nih.gov 301-496-2612 
Han-Yu Shih, Ph.D. Stadtman Investigator  han-yu.shih@nih.gov 301-402-5909
  1. Lim AI, McFadden T, Link VM, Han SJ, Karlsson RM, Stacy A, Farley TK, Harrison OJ, Shih HY, Cameron HA,Belkaid Y. Maternal Infection Promotes Offispring Tissue-Specific Immune Fitness. Biorxiv 2021
  2. 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 Mar 25.
  3. 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
  4. Fernando N, Sciumè G, O’Shea JJ, Shih HY. Multi-dimensional gene regulation in innate and adaptive lymphocytes: A view from regulomes. Frontiers in Immunology 2021
  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
  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. 2019
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  17. Sciumè G, Shih HY, Mikami Y, O'Shea JJ. Epigenomic views of innate lymphoid cells. Front Immunol. 2017. Reivew.
  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
  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
  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 *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
  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
  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
  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
  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
  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. Reivew.
  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. Reivew.
  28. Shih HY, Krangel MS. Chromatin architecture, CTCF and V(D)J recombination: managing long-distance relationships at antigen receptor loci. J Immunol. 2013
  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
  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
  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
  32. Shih HY, Hao B, Krangel MS. Orchestrating T-cell receptor a gene assembly through changes in chromatin structure and organization. Immunol Res. 2010
  33. Shih HY, Krangel MS. Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination. J Exp Med. 2010
  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