Lymphocyte Development

“We use lymphocytes and ES cells as models to study how gene expression patterns are established, transmitted through cell division and changed during development”

We study transcriptional and epigenetic mechanisms that underlie cellular differentiation and explore mechanisms of experimental reprogramming. Our core research activities include the following interrelated areas:

·       Reactivation of imprinted and X-linked genes in vitro and in vivo

·       Chromosome structure, Pc-G genes and epigenetic inheritance

·       The role of 3D genome organisation in gene expression and disease

·       Mechanisms of gene regulation by Ikaros and other transcription factor families

By combining classical cell biology and genetics approaches with current technologies we aim to understand how gene expression patterns are regulated during development as well as the consequences of mis-regulation in disease. This mechanistic information can provide a rationale for therapeutic intervention.

Lymphocyte Development

Flow sorting mouse chromosomes 19 and X

Selected Publications

Cuartero S, Weiss FD, Dharmalingam G, Guo Y, Ing-Simmons E, Masella S, Irene Robles-Rebollo, Xiao X, Wang Y-F, Barozzi I, Djeghloul D, Amano MT, Niskanen H, Petretto E, Dowell RD, Tachibana K, Kaikkonen MU, Nasmyth KA,  Lenhard B, Natoli G, Fisher AG & Merkenschlager M (2018) Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation Nature Immunology 19, 932–941

Cantone I, Dharmalingam G, Chan Y-W, Kohler A-C, Lenhard B, Merkenschlager M, Fisher AG (2017) Allele-specific analysis of cell fusion-mediated pluripotent reprograming reveals distinct and predictive susceptibilities of human X-linked genes to reactivationGenome Biology. 18, ISSN: 1474-760

Cantone I, Fisher AG (2017) Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease. Philosophical Transactions of the Royal Society B-Biological Sciences. 372, ISSN: 0962-8436

Liang Z, Brown KE, Carroll T, Taylor B, Ferreiros Vidal I, Hendrich B, Rueda D, Fisher AG, Merkenschlager M. (2017) A high-resolution map of transcriptional repressionElife, 6, ISSN:2050-084X. DOI: 10.7554/eLife.22767

Merkenschlager M, Nora EP. (2016) CTCF and Cohesin in Genome Folding and Transcriptional Gene Regulation, Annual Review of Genomics and Human Genetics. 17: 17-43, ISSN: 1527-8204

Van de Pette M, Abbas A, Feytout A, McNamara G, Bruno L, To WK, Dimond A, Sardini A, Webster Z, McGinty J, Paul EJ, Ungless MA, French PMW, Withers DJ, Uren A, Ferguson-Smith AC, Merkenschlager M, John RM, Fisher AG. (2017) Visualizing Changes in Cdkn1c Expression Links Early-Life Adversity to Imprint Mis-regulation in Adults. Cell Reports. 18(5):1090-1099. DOI: http://dx.doi.org/10.1016/j.celrep.2017.01.010

Fisher AG, Stumpf MPH, Merkenschlager M. (2017) Reconciling Epigenetic Memory and Transcriptional Responsiveness. Cell Syst. 4(4):373-374. doi: 10.1016/j.cels.2017.04.005. PMID: 28448796

Cantone, I., Bagci, H., Dormann, D., Dharmalingam, G., Nesterova, T., Brockdorff, N., Rougeulle, C., Vallot, C., Heard, E., Chaligne, R., Merkenschlager, M., Fisher, A.G., (2016). Ordered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming, Nature Communications. 7:12354 doi: 10.1038/ncomms12354.

Landeira, D., Bagci, H., Malinowski, A.R., Brown, K.E., Soza-Ried, J., Feytout, A., Webster, Z., Ndjetehe, E., Cantone, I., Asenjo, H.G., Brockdorff, N., Carroll, T., Merkenschlager, M., Fisher, A.G. et al., (2015). Jarid2 Coordinates Nanog Expression and PCP/Wnt Signaling Required for Efficient ESC Differentiation and Early Embryo Development, Cell Reports, Vol: 12, Pages: 573-586, ISSN: 2211-1247.

Ing-Simmons, E., Seitan, V.C., Faure, A.J., Flicek, P., Carroll, T., Dekker, J., Fisher, A.G., Lenhard, B., Merkenschlager, M. (2015). Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin. Genome Research, 25 (4), 504-513. ISSN: 1088-9051.

Lavagnolli, T., Gupta, P., Hoermanseder, E., Mira-Bontenbal, H., Dharmalingam, G., Carroll, T., Gurdon, J.B., Fisher, A.G., Merkenschlager, M. (2015). Initiation and maintenance of pluripotency gene expression in the absence of cohesin. Genes & Development, 29, 23-38. ISSN: 0890-9369.

Blevins, R., Bruno, L., Carroll, T., Elliott, J., Marcais, A., Loh, C., Hertweck, A., Krek, A., Rajewsky, N., Chen, C.-Z., Fisher, A.G., Merkenschlager, M. (2015). microRNAs Regulate Cell-to-Cell Variability of Endogenous Target Gene Expression in Developing Mouse Thymocytes. PLOS Genetics, 11. ISSN: 1553-7390.

Marcais, A., Blevins, R., Graumann, J., Feytout, A., Dharmalingam, G., Carroll, T., Amado, I.F., Bruno, L., Lee, K., Walzer, T., Mann, M., Freitas, A.A., Boothby, M., Fisher, A.G., Merkenschlager, M. (2014). microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells. Journal of Experimental Medicine, 211, 2281-2295. ISSN: 0022-1007.

Merkenschlager, M., Odom, D.T. (2013). CTCF and Cohesin: Linking Gene Regulatory Elements with Their Targets. CELL, 152 (6), 1285-1297. ISSN: 0092-8674.

Seitan, V. C., Faure, A. J., Zhan, Y., Patton, R., Lajoie, B. R., Ing-Simmons, E., Lenhard, B., Giorgetti, L., Heard, E., Fisher, A. G., Flicek, P., Dekker, J., Merkenschlager, M. (2013). Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments. Genome Research, 23 (12), 2066–2077.

Piccolo, F. M., Bagci, H., Brown, K. E., Landeira, D., Soza-Ried, J., Feytout, A., Mooijman, D., Hajkova, P., Leitch, H. G., Tada, T., Kriaucionis, S., Dawlaty, M. M., Jaenisch, R., Merkenschlager, M., Fisher, A. G. (2013). Different roles for tet1 and tet2 proteins in reprogramming-mediated erasure of imprints induced by EGC fusion. Molecular Cell, 49 (6), 1023–1033.

Tsubouchi, T., Soza-Ried, J., Brown, K., Piccolo, F. M., Cantone, I., Landeira, D., Bagci, H., Hochegger, H., Merkenschlager, M., Fisher, A. G., (2013). DNA synthesis is required for reprogramming mediated by stem cell fusion. Cell, 152 (4), 873–883.

Seitan, V. C., Hao, B., Tachibana-Konwalski, K., Lavagnolli, T., Mira-Bontenbal, H., Brown, K. E., Teng, G., Carroll, T., Terry, A., Horan, K., Marks, H., Adams, D. J., Schatz, D. G., Aragon, L., Fisher, A. G., Krangel, M. S., Nasmyth, K., Merkenschlager, M. (2011). A role for cohesin in t-cell-receptor rearrangement and thymocyte differentiation. Nature, 476 (7361), 467–471.

Jørgensen, H. F., Fisher, A. G. (2010). Can controversies be put to REST? Nature, 467(7311), E3.

Landeira, D., Sauer, S., Poot, R., Dvorkina, M., Mazzarella, L., Jørgensen, H. F., Pereira, F. F., Leleu, M., Piccolo, F. M., Spivakov, M., Brookes, E., Pombo, A., Fisher, C., Skarnes, W. C., Snoek, T., Bezstarosti, K., Demmers, J., Klose, R. J., Casanova, M., Tavares, L., Brockdorff, N., Merkenschlager, M., Fisher, A. G. (2010). Jarid2 is a PRC2 component in embryonic stem cells required for multi-lineage differentiation and recruitment of PRC1 and RNA polymerase II to developmental regulators. Nature Cell Biology, 12 (6), 618–624.

Pereira, C.F., Piccolo, F.M., Tsubouchi, T., Sauer, S., Ryan, N.K., Bruno, L., Landeira, D., Santos, J., Banito, A., Gil, J., Koseki, H., Merkenschlager, M., Fisher, A.G. (2010). ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell, 6 (6), 547–556.

Hadjur, S., Williams, L. M., Ryan, N. K., Cobb, B. S., Sexton, T., Fraser, P., Fisher, A. G., Merkenschlager, M. (2009). Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature, 460 (7253), 410–413.

Parelho, V., Hadjur, S., Spivakov, M., Leleu, M., Sauer, S., Gregson, H. C., Jarmuz, A., Canzonetta, C., Webster, Z., Nesterova, T., Cobb, B. S., Yokomori, K., Dillon, N., Aragon, L., Fisher, A. G., Merkenschlager, M. (2008). Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell, 132 (3), 422–433.