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Long-range gene regulation and 3D organization of the Glioblastoma Genome

Wallenberg Molecular Medicine Fellow: Cancer

The group is mainly focused on how the reprogramming of regulatory regions and topological changes in 3D chromatin organization determine gene dysregulation in glioblastoma, and how this subsequently contributes to malignancy, heterogeneity and invasiveness.

Research interest:

Glioblastoma is the most lethal and aggressive, but also the most common, of all primary brain tumors. Most genetic variants that predispose to cancer are located in non-coding regions enriched in putative enhancers, whose systematic rearrangements have a high impact on gene expression in cancer. Despite the number of susceptibility loci identified in glioblastoma, a functional understanding of how the non-coding regulatory genome contributes to the pathogenesis is missing.
We are interested in how the reprogramming of regulatory regions and topological changes in 3D chromatin organization determine gene dysregulation in glioblastoma. We intend to bring knowledge from different biological and technical backgrounds into the glioblastoma field, employing next generation sequencing approaches, genome editing and live-cell imaging in both glioblastoma mouse models and human glioma cell lines. The lab is focused on how the regulatory and topological architecture of the genome influences malignancy and integrates cues from the neurons in the tumor microenvironment to orchestrate gene expression in glioblastoma.

Strengths in lab:

My research background ranges from mouse models of cancer, mouse genetics, CRISPR-Cas9-based genome editing to a broad knowledge of "omics"-based approaches (e.g 4C-seq/HiC, ChIP-seq, RNA-seq), which I have mainly applied to the study of 3D chromatin organization and long-range gene regulation in the field of cancer. I have used Chromosome Conformation Capture methods to interrogate the 3D organization of chromatin and combined this with other genome-wide approaches, such as ChIP-seq and RNA-seq, to study the interplay with the epigenetic and transcriptional landscape, as well as with imaging and FISH methods to reach the single-cell resolution. In the lab we will combine state-of-the-art approaches in the fields of next generation sequencing and imaging, together with mouse models, 3D cultures and human samples from glioblastoma patients.

Selected publications:

- Bahr C*, von Paleske L*, Uslu VV*, Silvia Remeseiro, Takayama N, Ng SW, Murison A, Langenfeld K, Petretich M, Scognamiglio R, Zeisberger P, Benk AS, Amit I, Zandstra PW, Lupien M, Dick JE, Trumpp A, Spitz F. A Myc enhancer cluster regulates normal and leukaemic haemotopoietic stem cell hierarchies. Nature (2018) 553:515-520.

- Silvia Remeseiro*, Andreas Hörnblad*, François Spitz. Gene regulation during development in the light of topologically associating domains. Wiley Interdisciplinary Reviews Developmental Biology (2016). 5(2):169-85.

- Symmons O, Pan L, Silvia Remeseiro, Aktas T, Klein F, Huber W, Spitz F. The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances. Developmental Cell (2016) 39(5):529-543.

- Silvia Remeseiro, Cuadrado A, Carretero M, Martínez P, Drosopoulos WC, Cañamero M, Schildkraut CL, Blasco MA, Losada A. Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres. The EMBO Journal (2012) 31:2076-2089.

- Silvia Remeseiro*, Cuadrado A*, Gómez-López G, Pisano DG, Losada A. A unique role of cohesin-SA1 in gene regulation and development. The EMBO Journal (2012) 31:2090-2102.

- Cuadrado A, Silvia Remeseiro, Graña O, Pisano DG, Losada A. The contribution of cohesin-SA1 to gene expression and chromatin architecture in two murine tissues. Nucleic Acids Research (2015) 43(6):3056-3067.

- Silvia Remeseiro, Cuadrado A, Kawauchi S, Calof AL, Lander AD, Losada A. Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome. Biochimica et Biophysica Acta (2013) 3;1832(12):2097-2102.

- Cuadrado A, Silvia Remeseiro, Gómez-López G, Pisano DG, Losada A. The specific contributions of cohesin-SA1 to cohesion and gene expression: implications for cancer and development. Cell Cycle (2012) 11(12):2233-8.

- Silvia Remeseiro, Cuadrado A, Losada A. Cohesin in development and disease. Development (2013) 140(18):3715-8.

- Silvia Remeseiro and Ana Losada. Cohesin, a chromatin engagement ring. Current Opinion in Cell Biology (2013) 25(1):63-71.

- Carretero M, Silvia Remeseiro, Losada A. Cohesin ties up the genome. Current Opinion in Cell Biology (2010) 22(6):781-7.

- Lopez-Contreras AJ, Ruppen I, Nieto-Soler M, Murga M, Rodríguez-Acebes S, Silvia Remeseiro, Rodrigo-Perez S, Rojas AM, Mendez J, Muñoz J, Fernandez-Capetillo O. A proteomic characterization of factors enriched at nascent DNA molecules. Cell Reports (2013) 3(4):1105-16.

- Baquero-Montoya C, Gil-Rodríguez M, Teresa-Rodrigo M, Hernández-Marcos M, Bueno-Lozano G, Bueno-Martínez I, Silvia Remeseiro, Fernández-Hernández R, Bassecourt-Serra M, Rodríguez de Alba M, Queralt E, Losada A, Puisac B, Ramos F, Pié J. Could a patient with SMC1A duplication be classified as a human cohesinopathy? Clinical Genetics (2013) May 17. Doi: 10.1111/cge. 12194, 2014:85:446-451.

- Ruiz-Romero C, Carreira V, Rego I, Silvia Remeseiro, López-Armada MJ, Blanco FJ. Proteomic analysis of human osteoarthritic chondrocytes reveals protein changes in stress and glycolysis. Proteomics (2008) 8:495-507.

News

Three new WCMM Fellows
Three new WCMM Fellows

New group leaders will conduct research on brain tumors, prostate cancer and antimicrobial resistance

Opportunities

My group is currently searching for new group members, if you would like to know more please do not hesitate to contact me, silvia.remeseiro@umu.se