grupo

Group name: Epigenetics in Stem Cells and Cancer

    Group leader
  • David Landeira
  • Postdoctorals
  • Aurora Serrano Lopera
  • PHD Students
  • Amador Gallardo de los Reyes
  • Helena Gómez Asenjo
  • María Quintana Romero
  • Internships
  • Jose Javier Gómez Caballero
  • Antonio Valdivia Martínez
  • David Puerta Martos

SCIENTIFIC INTEREST AREAS

We study the role of epigenetic heterogeneity in the biology of stem cells and cancer.

We are a multidisciplinary group affiliated to the Department of Biochemistry and Molecular Biology II at University of Granada.

Additional information: http://www.landeiralab.es/

RESEARCH AREAS

  • We are interested in understanding how epigenetic cell-to-cell variability impacts early mammalian development and cancer progression. We use molecular and cellular biology tools combined with emerging bioinformatics platforms to study key biological systems. We use embryonic stem cells (ESCs) to study the role of epigenetics in the biology of pluripotent cells and human cell lines and patient samples to study the function of epigenetic factors in cancer progression.

    Epigenetic cell-to-cell variability in pluripotency

    ESCs are derived from the inner cell mass of blastocysts and provide a clonally self-renewing source of pluripotent cells that retain the potential to give rise to all cell types in an adult organism. ESCs and induced-pluripotent cells hold great promise for cell replacement therapies and disease modelling. However, pluripotent cells and derived counterparts display marked phenotypic heterogeneity that hampers their safe application in clinics. Importantly, defining the molecular basis of pluripotency is also a key challenge in basic developmental biology. ESCs display fluctuating levels of key determinants of the pluripotent state. Changes in gene transcription can result in protein fluctuation and therefore epigenetic regulation is crucial in the creation of cell-to-cell variability in genetic clonal populations. However, identification of epigenetic regulators involved and their mode of action has been hindered due to technical limitations. Combination of genome-wide analysis of the epigenome with single-cell gene expression data has established that chromatin factors can regulate cell-to-cell variability in ESCs. More recent genome-wide studies of individual cells are beginning to show that gene expression and the epigenome can be highly variable in pluripotent stem cells.

    Epigenetic intratumor heterogeneity

    At cancer diagnose tumors are composed of tens of millions of cells that have already diversified producing heterogeneous cell populations. Intratumoral heterogeneity (ITH) has been observed in solid tumors and leukemia where it has been used to model tumor evolution and thus improving our understanding of tumorigenesis.  However a majority of cancer therapies still fail to achieve durable responses which is often attributed to underlying ITH. Genetic alterations have been traditionally identified like the main drivers of ITH. However, emerging literature show that in cell populations with high degree of genetic homogeneity, epigenetic heterogeneity can lead to cell-to-cell variability in response to therapy. Additionally, genes encoding regulators of the epigenome are among the most commonly mutated genes in different cancer types. Thus, epigenetic ITH is increasingly appreciated as a determinant of treatment failure and disease recurrence.

     

    Currently we are developing a set of projects to depict epigenetic heterogeneity and associated chromatin regulators that is critical for pluripotency function and cancer progression. We aim to characterize novel regulatory aspects that will be key to understand early human development, to move pluripotent cells to the clinics and to develop more personalized and precise strategies in cancer treatment. 

FUNDING

  • Universidad de Granada
  • Ministerio de Economía y Competitividad

SELECTED PUBLICATIONS

Landeira D, Bagci H, Malinowsky AR, Brown K, Soza-Ried J, Feytout A, Webster Z, Ndjetehe E, Cantone I, Asenjo HG, Brockdorff N, Carroll T, Merkenschlager M, Fisher AG. Jarid2 co-ordinates Nanog expression and PCP/Wnt signalling required for efficient ESC differentiation and early embryo development. Cell Reports 12, 573-586 (2015). Abstract.

Piccolo FM, Bagci H, Brown K, Landeira D, Soza-Ried J, Feytout A, Moojman D, Hajkova P, Leitch HG, Tada T, Kriaucionis S, Dawlaty MD, Jaenisch R, Merkenschlager M and Fisher AG. Different roles for Tet1 and Tet2 proteins in reprogramming-mediated erasure of imprints induced by EG cell fusion. Mol Cell, 49, 1023-1033 (2013). Abstract.

Tsubouchi T, Soza-Ried J, Brown K, Piccolo FM, Cantone I, Landeira D, Bagci H, Hochegger H, Merkenschlager M and Fisher AG. DNA synthesis is required for reprogramming mediated by stem cell fusion. Cell 14;152(4):873-83 (2013). Abstract.

Landeira D and Fisher AG. Inactive yet indispensable; the tale of Jarid2. Trends Cell Biol 21(2):74-80 (2011). Abstract.

Landeira D, Sauer S, Poot R, Dvorkina M, Mazzarella L, Jorgensen 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 and Fisher AG. 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. Nat Cell Biol 12 (6):618-624 (2010). Abstract.

Pereira CF, Piccolo FM, Tsubouchi T, Sauer S, Ryan NK, Bruno L, Landeira D, Santos J, Banito A, Gil J, Koseki H, Merkenschlager M and Fisher AG. ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency. Cell Stem Cell 6(6): 547-556 (2010). Abstract. Click here for an updated list of publications.