Jane Skok, Ph.D.

Principal Investigator

After completing my undergraduate degree in Microbiology and Genetics at University College London, 1979, I went on to do a PhD at Imperial Cancer Research Fund, Lincoln's Inn Fields (now part of Cancer Research UK). During this period I made the surprising discovery that different genes encode for serum and fibroblast C1q, a component of the complement pathway. These findings were published in Nature:

Skok J, Solomon E, Reid KB, Thompson RA. (1981) Distinct genes for fibroblast and serum C1q. Nature. Aug 6;292(5823):549-51.

My career then followed a rather non-conventional track as I left science for 12 years in 1984 to take care of my daughter who was chronically ill.

Skok JA. Taking a break from the lab: can it really be done? Trends Cell Biol. 2014 Dec;24(12):725-6.

When I returned it was necessary to retrain and to this end I undertook a Masters degree, which provided a stepping stone to return to the lab. I was subsequently awarded a 4 year Wellcome Trust Career re-entry grant which funded my postdoc. I joined David Gray's lab at Imperial College London as a postdoctoral fellow to investigate whether B cells could control the differentiation potential of T cells. Indeed, our studies were the first to show that B cells, like T cells have a regulatory capacity.

Skok J, Poudrier J, Gray D. (1999) Dendritic cell-derived IL-12 promotes B cell induction of Th2 differentiation: a feedback regulation of Th1 development. J. Immunology Oct 15;163(8):4284-91.

When David Gray relocated to Edinburgh University I moved to Mandy Fisher's lab to continue my postdoc investigating how nuclear organization of the antigen receptor genes regulate V(D)J recombination and allelic exclusion. This move ignited my interest in the role of nuclear organization in controlling gene regulation and since this time my lab has been at the forefront of these studies.

Skok JA, Brown KE, Azuara V, Caparros ML, Baxter J, Takacs K, Dillon N, Gray D, Perry RP, Merkenschlager M, Fisher AG. (2001) Nonequivalent nuclear location of immunoglobulin alleles in B lymphocytes. Nature Immunology Sep;2(9):848-54.

I received a highly competitive University Award, associated with a tenured position to start my own lab at University College London in 2002. Funding for my lab was supplemented with two consecutive Wellcome Trust Project grants (the equivalent of an NIH renewal. Details can be found on ORCID, http://orcid.org/0000-0002-4145-1516). In my new lab I continued to investigate the contribution of nuclear organization in regulating B cell development and elucidated the roles of Pax5, locus contraction, and nuclear subcompartmentalization in recombination.

Fuxa, M*., Skok, J*., Souabni, A., Salvagiotto, G., Roldan, E. & Busslinger. Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004 Feb 15;18(4):411-22. * Equal first.

Roldan, E., Fuxa, M., Chong, W., Martinez, D., Novatchkova, M., Busslinger, M. & Skok, J.A. Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nat Immunol. 2005 Jan;6(1):31-41.

Goldmit M*, Ji Y*, Skok J*, Roldán E, Jung S, Cedar H, Bergman Y. (2005) Epigenetic ontogeny of the k locus during B cell development.  Nature Immmunology 6(2):198-203. (*Joint first authorship).

Skok JA, Gisler R, Novatchkova M, Farmer D, de Laat W, Busslinger M: Reversible contraction by looping of the Tcra and Tcrb loci in rearranging thymocytes. Nature Immunology 2007, 8:378-387.

In 2006 I was recruited to New York University School of Medicine, where my lab became interested in trying to understand the contribution of nuclear organization in controlling RAG cleavage activity. Tight control of V(D)J recombination is essential to prevent the occurrence of genetic anomalies that drive cellular transformation. One level at which this is regulated is control of RAG expression. We identified a role for IL-7 in negatively regulating Rag expression in cycling cells, which is important for maintaining genome stability. Another important aspect is control of cleavage in individual cells. It has been known for some time that inter-locus rearrangements between antigen receptor loci and other forms of chromosomal instability are a hallmark of tumors found in ATM deficient mice and A-T patients. In addition tumors from p53-/-Rag2core/core mice (p53-/- mice lacking the C terminus if RAG2) have a similar phenotype. However, the mechanisms underlying these chromosomal rearrangements were not elucidated. Our studies show that a defect in feedback control of RAG2 activity gives rise to breaks on different loci in the same T cell, which provides a direct mechanism for generating these aberrant rearrangements. Both the RAG2 C-terminus and ATM prevent bi-allelic and bi-locus RAG-mediated cleavage through modulation of 3D conformation and nuclear organization of the two loci. This limits the number of potential substrates for translocation and provides an important mechanism for protecting genome stability.

Hewitt, S.L., Yin, B., Ji, Y., Chaumeil, J., Marszalek, K., Tenthorey, J., Salvagiotto, G., Steinel, N., Ramsey, L.B., Ghysdael, J., Farrar, M.A., Sleckman, B.P., Schatz, D.G., Busslinger, M., Bassing, C.H. & Skok, J.A. RAG-1 and ATM coordinate monoallelic recombination and nuclear positioning of immunoglobulin loci. Nat Immunol. 2009 Jun;10(6):655-64.

Chaumeil, J., Micsinai, M., Ntziachristos, P., Roth, D.B., Aifantis, I., Kluger, Y., Deriano, L. & Skok, J.A. The RAG2 C-terminus and ATM protect genome integrity by controlling antigen receptor gene cleavage. Nat Commun. 2013;4:2231..

Chaumeil, J., Micsinai, M., Ntziachristos, P., Deriano, L., Wang, J.M., Ji, Y., Nora, E.P., Rodesch, M.J., Jeddeloh, J.A., Aifantis, I., Kluger, Y., Schatz, D.G. & Skok, J.A. Higher-order looping and nuclear organization of Tcra facilitate targeted rag cleavage and regulated rearrangement in recombination centers. Cell Reports. 2013 Feb 21;3(2):359-70.

Another long-standing interest of my lab has been to understand how genes can be controlled via long-range sharing of regulatory elements. In this context we have demonstrated in a number of studies that the enhancers of one locus can impact the regulation of another locus located megabases away on the same chromosome, or on a different chromosome altogether.

Hewitt, S.L., Farmer, D., Marszalek, K., Cadera, E., Liang, H.E., Xu, Y., Schlissel, M.S. and Skok, J.A. (2008) Association between the Igk and Igh immunoglobulin loci mediated by the 3' Igk enhancer induces 'decontraction' of the Igh locus in pre-B cells. Nat Immunol, 9, 396-404.

Collins, A., Hewitt, S.L., Chaumeil, J., Sellars, M., Micsinai, M., Allinne, J., Parisi, F., Nora, E.P., Bolland, D.J., Corcoran, A.E., Kluger, Y., Bosselut, R., Ellmeier, W., Chong, M.M., Littman, D.R. & Skok, J.A. RUNX transcription factor-mediated association of Cd4 and Cd8 enables coordinate gene regulation. Immunity. 2011 Mar 25;34(3):303-14.

Proudhon, C., Snetkova, V., Raviram, R., Lobry, C., Badri, S., Jiang, T., Hao, B., Trimarchi, T., Kluger, Y., Aifantis, I., Bonneau, R., Skok, J.A. Active and inactive enhancers co-operate to exert localized and long-range control of gene regulation. Cell reports, (2016).

There is gap in productivity from 2013 that can be explained by the disruption of Hurricane Sandy when my lab was shut down for ten months.

Expertise: My laboratory applies a combination of sophisticated imaging techniques, molecular biology, genetics, and immunology to investigate the contribution of nuclear organization and long-range interactions in coordinating transcriptional programs, recombinational events and the maintenance of genome stability in developing lymphocytes. Since starting my lab I have continued to pioneer new applications of 3-D FISH and have set up a highly innovative CRISPR/Cas9 live imaging system. In addition I independently established chromosome conformation capture at NYU and developed a method for 4C-seq analysis, 4C-ker and for detecting multi-loci interactions. Thus, we are one of a handful of labs that has expertise in both the experimental and analytical aspects of chromosome folding. My lab shares its knowledge widely with the scientific community both inside and outside of NYU as demonstrated by our numerous collaborative publications.

Goals: The focus of my lab has now shifted almost entirely to investigating the impact of nuclear organization in altering gene regulation in specific cancer settings. We have the advantage in this emerging field of being able to apply our unique skills to this question.