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 reactivation. Genome Biology 18, ISSN: 1474-760.

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 repression. Elife 6, ISSN:2050-084X. DOI: 10.7554/eLife.22767.

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.

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.

Cantone I, Bagci H, Dormann D, Dharmalingam G, Nesterova T, Brockdorff N, Rougeulle C, Vallot C, Heard E, Chaligne R, Merkenschlager M, Fisher AG. (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 AR, Brown KE, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG. (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 VC, Faure AJ, Flicek P, Carroll T, Dekker J, Fisher AG, 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, Hörmanseder E, Mira-Bontenbal H, Dharmalingam G, Carroll T, Gurdon JB, Fisher AG, 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 CZ, Fisher AG, 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 IF, Bruno L, Lee K, Walzer T, Mann M, Freitas AA, Boothby M, Fisher AG, 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 DT. (2013). CTCF and Cohesin: Linking Gene Regulatory Elements with Their Targets Cell 152 (6), 1285-1297. ISSN: 0092-8674.

Seitan VC, Faure AJ, Zhan Y, McCord RP, Lajoie BR, Ing-Simmons E, Lenhard B, Giorgetti L, Heard E, Fisher AG, 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 FM, Bagci H, Brown KE, Landeira D, Soza-Ried J, Feytout A, Mooijman D, Hajkova P, Leitch HG, Tada T, Kriaucionis S, Dawlaty MM, Jaenisch R, Merkenschlager M, Fisher AG. (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 FM, Cantone I, Landeira D, Bagci H, Hochegger H, Merkenschlager M, Fisher AG. (2013). DNA synthesis is required for reprogramming mediated by stem cell fusion. Cell 152 (4), 873–883.

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

Jørgensen HF, Fisher AG. (2010). Can controversies be put to REST? Nature 467(7311), E3.

Landeira D, Sauer S, Poot R, Dvorkina M, Mazzarella L, Jørgensen HF, Pereira CF, Leleu M, Piccolo FM, Spivakov M, Brookes E, Pombo A, Fisher C, Skarnes WC, Snoek T, Bezstarosti K, Demmers J, Klose RJ, Casanova M, Tavares L, Brockdorff N, Merkenschlager M, Fisher AG. (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 CF, Piccolo FM, Tsubouchi T, Sauer S, Ryan NK, Bruno L, Landeira D, Santos J, Banito A, Gil J, Koseki H, Merkenschlager M, Fisher AG. (2010). ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell 6 (6), 547–556.

Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, Fisher AG, 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 HC, Jarmuz A, Canzonetta C, Webster Z, Nesterova T, Cobb BS, Yokomori K, Dillon N, Aragon L, Fisher AG, Merkenschlager M. (2008). Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell 132 (3), 422–433.