Kim HJ, Li P, Kim T, Oldfield AJ, Zheng X, Yang P.
Biology of distal regulatory elements
Cell identity is achieved, in large part, as a consequence of specific gene expression patterns. While core promoters are sufficient to drive basal expression, promoter-distal regulatory elements (DREs), such as enhancers, regulate spatio-temporal control of gene expression. These key regulatory elements are critical determinants of development and disease and their importance in cell identity determination also implies that they risk being hijacked, leading to transcriptome re-wiring and the establishment of detrimental cellular programs, such as cancer. Therefore, identifying the actors and understanding the mechanisms that lead to enhancer activation during cell-identity changes is imperative if we are to prevent such phenomena.
In order to understand how cell-type-specific enhancers play an essential role during cellular identity transitions we use a dynamic model of cell reprogramming: the Epithelial-to-Mesenchymal Transition (EMT).
Approximately 90% of all human cancers are of epithelial origin (carcinomas). Epithelial cells form monolayers of tightly attached and highly differentiated cells with little invasive potential. It has been proposed that malignant epithelial cells acquire migratory, invasive and stem cell properties through a well-regulated cell reprogramming process, the EMT. Over the course of this process, epithelial cells acquire a less differentiated, more apoptosis-resistant and motile phenotype that allows the cells to enter the blood or lymphatic vessels to colonize distant organs, leading to tumor metastasis. The EMT is also a reversible phenomenon through the mesenchymal-to-epithelial transition (MET), thought to affect circulating cancer cells when they reach a desirable metastatic niche to develop secondary tumors. Notably, the EMT has also been suggested to be an important source of cancer stem cells that could be responsible for the reappearance, after long periods of remission, of dormant metastasized and treatment-resistant tumor cells.
Our team uses both cutting-edge genome-wide and locus-specific methods to functionally dissect distal regulatory elements and gain a better understanding of all the ways that these distant, non-coding regulatory units can affect gene regulation and cell identity as a whole.
PUBLICATIONS OF THE TEAM
Barral A, Pozo G, Ducrot L, Papadopoulos GL, Sauzet S, Oldfield AJ, Cavalli G, Déjardin J.
Segelle A, Núñez-Álvarez Y, Oldfield AJ, Webb KM, Voigt P, Luco RF.
Lorenzi C, Barriere S, Arnold K, Luco RF, Oldfield AJ, Ritchie W.
Kumar D, Cinghu S, Oldfield AJ, Yang P, Jothi R.
Villemin JP, Lorenzi C, Cabrillac MS, Oldfield A, Ritchie W, Luco RF.
Agirre E, Oldfield AJ, Bellora N, Segelle A, Luco RF.
Broseus L, Thomas A, Oldfield AJ, Severac D, Dubois E, Ritchie W.
Kim HJ, Osteil P, Humphrey SJ, Cinghu S, Oldfield AJ, Patrick E, Wilkie EE, Peng G, Suo S, Jothi R, Tam PPL, Yang P.
Oldfield AJ*, Henriques T, Kumar D, Burkholder AB, Cinghu S, Paulet D, Bennett BD, Yang P, Scruggs BS, Lavender CA, Rivals E, Adelman K*, Jothi R*.
Yang P, Humphrey SJ, Cinghu S, Pathania R, Oldfield AJ, Kumar D, Perera D, Yang JYH, James DE, Mann M, Jothi R.
Cinghu S, Yang P, Kosak JP, Conway AE, Kumar D, Oldfield AJ, Adelman K, Jothi R.
Yang P, Oldfield A, Kim T, Yang A, Yang JYH, Ho JWK.
Makhlouf M*, Ouimette JF*, Oldfield A*, Navarro P, Neuillet D, Rougeulle C.
Oldfield AJ, Yang P, Conway AE, Cinghu S, Freudenberg JM, Yellaboina S, Jothi R.
Cinghu S, Yellaboina S, Freudenberg JM, Ghosh S, Zheng X, Oldfield AJ, Lackford BL, Zaykin DV, Hu G, Jothi R.
Navarro P, Oldfield A, Legoupi J, Festuccia N, Dubois A, Attia M, Schoorlemmer J, Rougeulle C, Chambers I, Avner P.
Fardeau V, Lelandais G, Oldfield A, Salin HN, Lemoine S, Garcia M, Tanty V, Le Crom S, Jacq C, Devaux F.