Overview

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.
  • Dissecting mechanistic details of transcriptional activation.
  • 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:

Staff

Chief
Head, NIH Regulome Project
301-402-7858
Postdoctoral Fellow (Visiting)
301-451-6060
Postdoctoral Fellow
301-435-3052
Staff Scientist
301 435 1514
Postdoctoral Fellow (Visiting)
301-451-7422
Postdoctoral Fellow
301-451-7422
Postdoctoral Fellow (Visiting)
301-451-7422
Research Fellow
301-402-7929
Postdoctoral Fellow (Visiting)
301-435-3052
Postdoctoral Fellow (Visiting)
301-435-3052
Postdoctoral Fellow (Visiting)
301-435-3052
Research Fellow
301-594-6675
Postdoctoral Fellow (Visiting)
301-480-5852

Image & Media Gallery

Scientific Publications

Selected Recent Publications

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
Nature.
2021 Feb 10;
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
Nature.
2020 Oct;
586(7828).
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
Nature.
2019 Nov;
575(7782).
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
Cell.
2019 Aug 22;
178(5).
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
Cell.
2018 May 17;
173(5).
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
Cell.
2014 Dec 18;
159(7).
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
Cell.
2013 Dec 19;
155(7).
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
Cell.
2013 May 23;
153(5).
doi: 10.1016/j.cell.2013.04.033
PMID: 23706737

News & Highlights

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Last Updated: March 2021