Integrative Analysis Reveals Histone Demethylase LSD1 Promotes RNA Polymerase II Pausing
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
SETDB1/NSD-dependent H3K9me3/H3K36me3 dual heterochromatin maintains gene expression profiles by bookmarking poised enhancers.
Barral A, Pozo G, Ducrot L, Papadopoulos GL, Sauzet S, Oldfield AJ, Cavalli G, Déjardin J.
Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing.
Segelle A, Núñez-Álvarez Y, Oldfield AJ, Webb KM, Voigt P, Luco RF.
Decoding the function of bivalent chromatin in development and cancer.
Kumar D, Cinghu S, Oldfield AJ, Yang P, Jothi R.
NF-Y controls fidelity of transcription initiation at gene promoters through maintenance of the nucleosome-depleted region.
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*.
Multi-omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency.
Yang P, Humphrey SJ, Cinghu S, Pathania R, Oldfield AJ, Kumar D, Perera D, Yang JYH, James DE, Mann M, Jothi R.
Intragenic Enhancers Attenuate Host Gene Expression
Cinghu S, Yang P, Kosak JP, Conway AE, Kumar D, Oldfield AJ, Adelman K, Jothi R.
A prominent and conserved role for YY1 in Xist transcriptional activation.
Makhlouf M*, Ouimette JF*, Oldfield A*, Navarro P, Neuillet D, Rougeulle C.
Histone-fold domain protein NF-Y promotes chromatin accessibility for cell type-specific master transcription factors.
Oldfield AJ, Yang P, Conway AE, Cinghu S, Freudenberg JM, Yellaboina S, Jothi R.
Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis
Cinghu S, Yellaboina S, Freudenberg JM, Ghosh S, Zheng X, Oldfield AJ, Lackford BL, Zaykin DV, Hu G, Jothi R.