Senior Investigator

John O’Shea, M.D.

NIAMS Scientific Director

Our main goal is to unravel the nuclear events that drive activation and transformation of B lymphocytes, from changes in transcription, epigenetics and chromatin architecture, to recombination and hypermutation of antibody genes. To achieve these goals, our team combines a wide range of cutting-edge technologies, including genome editing, nanoscopy, in situ Hi-C, cryo-EM, and bioinformatic tools.

B lymphocytes in higher organisms develop in the bone marrow, where they recombine and assemble their cell surface antibody receptor genes. Upon migration to peripheral organs, antibody receptors may bind foreign proteins that belong to pathogens. This recognition leads to a second round of DNA recombination that changes the antibody class, from IgM to IgG, IgE, or IgA. We call this process class switch recombination.

Scientific chart with 3D rendered structure
To explore transcriptional regulation in mammalian cells, we are implementing in situ Hi-C, epigenomics, and cryo-EM techniques among others.

In addition, the antibody genes are hypermutated during the immune response, a phenomenon which coupled to selection improves the capacity of B cells to recognize pathogens.

Aside from antibody receptor genes, recombination and hypermutation can promiscuously target other loci in the B cell genome. This can lead to deregulation of transcription and B cell tumor development. Our laboratory has developed several assays to visualize and study such promiscuous activity at susceptible sites.

Our current interests involve:

  • Understanding the impact of nuclear architecture on B cell gene expression and transformation.
  • Dissecting mechanistic details of chromosomal translocations.
  • The production of new mouse models to generate human antibodies of clinical interest.

The Regulome Project

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The NIH Regulome Project was established in 2010 as an ongoing collaboration of intramural and invited extramural research groups.

Its primary goal is to understand transcriptional regulation in mammalian systems using cutting-edge technologies, including Hi-C and derivatives, single-molecule microscopy, real-time transcriptional assays, cryo-EM, genomics, biological modeling, CRISPR-Cas9 genetic screens, neural networks, and biophysics.

Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:

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Scientific Publications

Selected Recent Publications

"Stripe" transcription factors provide accessibility to co-binding partners in mammalian genomes.

Zhao Y, Vartak SV, Conte A, Wang X, Garcia DA, Stevens E, Kyoung Jung S, Kieffer-Kwon KR, Vian L, Stodola T, Moris F, Chopp L, Preite S, Schwartzberg PL, Kulinski JM, Olivera A, Harly C, Bhandoola A, Heuston EF, Bodine DM, Urrutia R, Upadhyaya A, Weirauch MT, Hager G, Casellas R
Mol Cell.
2022 Sep 15;
doi: 10.1016/j.molcel.2022.06.029
PMID: 35863348

BRD2 compartmentalizes the accessible genome.

Xie L, Dong P, Qi Y, Hsieh TS, English BP, Jung S, Chen X, De Marzio M, Casellas R, Chang HY, Zhang B, Tjian R, Liu Z
Nat Genet.
2022 Apr;
doi: 10.1038/s41588-022-01044-9
PMID: 35410381

Nanobodies from camelid mice and llamas neutralize SARS-CoV-2 variants.

Xu J, Xu K, Jung S, Conte A, Lieberman J, Muecksch F, Lorenzi JCC, Park S, Schmidt F, Wang Z, Huang Y, Luo Y, Nair MS, Wang P, Schulz JE, Tessarollo L, Bylund T, Chuang GY, Olia AS, Stephens T, Teng IT, Tsybovsky Y, Zhou T, Munster V, Ho DD, Hatziioannou T, Bieniasz PD, Nussenzweig MC, Kwong PD, Casellas R
2021 Jul;
doi: 10.1038/s41586-021-03676-z
PMID: 34098567

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.

Wang Z, Schmidt F, Weisblum Y, Muecksch F, Barnes CO, Finkin S, Schaefer-Babajew D, Cipolla M, Gaebler C, Lieberman JA, Oliveira TY, Yang Z, Abernathy ME, Huey-Tubman KE, Hurley A, Turroja M, West KA, Gordon K, Millard KG, Ramos V, Da Silva J, Xu J, Colbert RA, Patel R, Dizon J, Unson-O'Brien C, Shimeliovich I, Gazumyan A, Caskey M, Bjorkman PJ, Casellas R, Hatziioannou T, Bieniasz PD, Nussenzweig MC
2021 Apr;
doi: 10.1038/s41586-021-03324-6
PMID: 33567448

CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.

Ba Z, Lou J, Ye AY, Dai HQ, Dring EW, Lin SG, Jain S, Kyritsis N, Kieffer-Kwon KR, Casellas R, Alt FW
2020 Oct;
doi: 10.1038/s41586-020-2578-0
PMID: 32717742

Fundamental roles of chromatin loop extrusion in antibody class switching.

Zhang X, Zhang Y, Ba Z, Kyritsis N, Casellas R, Alt FW
2019 Nov;
doi: 10.1038/s41586-019-1723-0
PMID: 31666703

A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers.

El Khattabi L, Zhao H, Kalchschmidt J, Young N, Jung S, Van Blerkom P, Kieffer-Kwon P, Kieffer-Kwon KR, Park S, Wang X, Krebs J, Tripathi S, Sakabe N, Sobreira DR, Huang SC, Rao SSP, Pruett N, Chauss D, Sadler E, Lopez A, Nóbrega MA, Aiden EL, Asturias FJ, Casellas R
2019 Aug 22;
doi: 10.1016/j.cell.2019.07.011
PMID: 31402173

The Energetics and Physiological Impact of Cohesin Extrusion.

Vian L, Pękowska A, Rao SSP, Kieffer-Kwon KR, Jung S, Baranello L, Huang SC, El Khattabi L, Dose M, Pruett N, Sanborn AL, Canela A, Maman Y, Oksanen A, Resch W, Li X, Lee B, Kovalchuk AL, Tang Z, Nelson S, Di Pierro M, Cheng RR, Machol I, St Hilaire BG, Durand NC, Shamim MS, Stamenova EK, Onuchic JN, Ruan Y, Nussenzweig A, Levens D, Aiden EL, Casellas R
2018 May 17;
doi: 10.1016/j.cell.2018.03.072
PMID: 29706548

B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity.

Qian J, Wang Q, Dose M, Pruett N, Kieffer-Kwon KR, Resch W, Liang G, Tang Z, Mathé E, Benner C, Dubois W, Nelson S, Vian L, Oliveira TY, Jankovic M, Hakim O, Gazumyan A, Pavri R, Awasthi P, Song B, Liu G, Chen L, Zhu S, Feigenbaum L, Staudt L, Murre C, Ruan Y, Robbiani DF, Pan-Hammarström Q, Nussenzweig MC, Casellas R
2014 Dec 18;
doi: 10.1016/j.cell.2014.11.013
PMID: 25483777

Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation.

Kieffer-Kwon KR, Tang Z, Mathe E, Qian J, Sung MH, Li G, Resch W, Baek S, Pruett N, Grøntved L, Vian L, Nelson S, Zare H, Hakim O, Reyon D, Yamane A, Nakahashi H, Kovalchuk AL, Zou J, Joung JK, Sartorelli V, Wei CL, Ruan X, Hager GL, Ruan Y, Casellas R
2013 Dec 19;
doi: 10.1016/j.cell.2013.11.039
PMID: 24360274

Global regulation of promoter melting in naive lymphocytes.

Kouzine F, Wojtowicz D, Yamane A, Resch W, Kieffer-Kwon KR, Bandle R, Nelson S, Nakahashi H, Awasthi P, Feigenbaum L, Menoni H, Hoeijmakers J, Vermeulen W, Ge H, Przytycka TM, Levens D, Casellas R
2013 May 23;
doi: 10.1016/j.cell.2013.04.033
PMID: 23706737

News & Highlights

Announcement |

Scientific Director of Intramural Research, Dr. John O'Shea, Elected to the U.S. National Academy of Sciences

On May 2, 2023, NIAMS Scientific Director of Intramural Research, 

Announcement |

NIAMS’ John O’Shea Awarded 2021 Harrington Prize for Innovation in Medicine

For his groundbreaking work in immunology, John J. O’Shea, M.D., will receive the eighth annual Harrington Prize for Innovation in Medicine.