Biology of distal regulatory elements

Genome dynamics

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.

Andrew OLDFIELD
attached to the direction
Researcher

PUBLICATIONS OF THE TEAM

Integrative Analysis Reveals Histone Demethylase LSD1 Promotes RNA Polymerase II Pausing

Kim HJ, Li P, Kim T, Oldfield AJ, Zheng X, Yang P.

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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.

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Histone marks regulate the epithelial-to-mesenchymal transition via alternative splicing.

Segelle A, Núñez-Álvarez Y, Oldfield AJ, Webb KM, Voigt P, Luco RF.

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IRFinder-S: a comprehensive suite to discover and explore intron retention.

Lorenzi C, Barriere S, Arnold K, Luco RF, Oldfield AJ, Ritchie W.

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Decoding the function of bivalent chromatin in development and cancer.

Kumar D, Cinghu S, Oldfield AJ, Yang P, Jothi R.

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A cell-to-patient machine learning transfer approach uncovers novel basal-like breast cancer prognostic markers amongst alternative splice variants.

Villemin JP, Lorenzi C, Cabrillac MS, Oldfield A, Ritchie W, Luco RF.

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Splicing-associated chromatin signatures: a combinatorial and position-dependent role for histone marks in splicing definition

Agirre E, Oldfield AJ, Bellora N, Segelle A, Luco RF.

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TALC: Transcript-level Aware Long-read Correction.

Broseus L, Thomas A, Oldfield AJ, Severac D, Dubois E, Ritchie W.

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Transcriptional network dynamics during the progression of pluripotency revealed by integrative statistical learning.

Kim HJ, Osteil P, Humphrey SJ, Cinghu S, Oldfield AJ, Patrick E, Wilkie EE, Peng G, Suo S, Jothi R, Tam PPL, Yang P.

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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*.

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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.

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Intragenic Enhancers Attenuate Host Gene Expression

Cinghu S, Yang P, Kosak JP, Conway AE, Kumar D, Oldfield AJ, Adelman K, Jothi R.

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Integrative analysis identifies co-dependent gene expression regulation of BRG1 and CHD7 at distal regulatory sites in embryonic stem cells.

Yang P, Oldfield A, Kim T, Yang A, Yang JYH, Ho JWK.

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A prominent and conserved role for YY1 in Xist transcriptional activation.

Makhlouf M*, Ouimette JF*, Oldfield A*, Navarro P, Neuillet D, Rougeulle C.

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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.

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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.

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Molecular coupling of Tsix regulation and pluripotency.

Navarro P, Oldfield A, Legoupi J, Festuccia N, Dubois A, Attia M, Schoorlemmer J, Rougeulle C, Chambers I, Avner P.

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The central role of PDR1 in the foundation of yeast drug resistance.

Fardeau V, Lelandais G, Oldfield A, Salin HN, Lemoine S, Garcia M, Tanty V, Le Crom S, Jacq C, Devaux F.

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GAUBERT Nicolas
GAUBERT Nicolas
Ancien stagiaire IGH
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EDUCATION

2010 PhD
Université Paris VI, Pierre et Marie Curie, France. Supervised by: Dr. Claire Rougeulle.

2006 Master’s
Genomes, Cells, Development & Evolution, specialised in Genomics. Université Paris XI, Orsay, France

CURRENT POSITION

Since 2022 – Independent Project Leader. Biology of distal regulatory elements group.
Department of Genome Dynamics, Institut de Génétique Humaine, CNRS UMR9002, Université de Montpellier, France.

Since 2018 – Permanent researcher – CNRS CRCN
Department of Genome Dynamics, Institut de Génétique Humaine, CNRS UMR9002, Université de Montpellier, France.

PREVIOUS POSITIONS

2018-2022

CNRS permanent researcher: Epigenetics and Splicing group, Institute of Human Genetics, UMR9002, Montpellier, France.

Subject: The role of chromatin tri-dimensional structure in alternative splicing.

Supervised by Dr. Reini Fernandez de Luco.

2016-2018

Post-doctoral fellow: Epigenetics and Splicing group, Institute of Human Genetics, UMR9002, Montpellier, France.

Subject: The role of chromatin tri-dimensional structure in alternative splicing.

Mentored by Dr. Reini Fernandez de Luco.

2012-2016

Post-doctoral fellow: Systems Biology Group, Epigenetics and Stem Cell Biology Laboratory, NIEHS, NIH, Research Triangle Park, North Carolina, USA.

Subject: Studying the role of the NF-Y complex in the maintenance of murine embryonic stem cell cellular identity.

Mentored by Dr. Raja Jothi.

2011-2012

Post-doctoral fellow: Genome Organization and Function Laboratory, University College London Cancer Institute, London, United Kingdom.

Subject: Cohesin’s role in transcriptional regulation and tridimensional chromatin architecture.

Mentored by Dr. Suzana Hadjur.

2010-2011

Post-doctoral fellow: Laboratory of Non-coding RNAs, Differentiation and Development, Epigenetics and Cell Fate Unit, UMR7216, Université Paris VII - Diderot, France.

Subject: Study of the Xist transcriptional network in murine embryonic stem cells.

Mentored by Dr. Claire Rougeulle.

2006-2010

PhD student: Mouse Molecular Genetics Laboratory, Institut Pasteur of Paris, directed by Pr. Philip Avner (2006-2008), Laboratory of Non-coding RNAs, Differentiation and Development, Epigenetics and Cell Fate Unit, UMR7216, Université Paris VII - Diderot, France. (2009-2010).

Subject: Study of the Xist transcriptional network in murine embryonic stem cells.

Mentored by Dr. Claire Rougeulle.

2006-2009

Teaching Assistant: Cellular Biology. Université Paris VI - Pierre et Marie Curie, France.

2006

Research Assistant: Laboratory of Molecular Genetics, École Normale Supérieure of Paris. Directed by Pr. Claude Jacques.

Subject: Modifications of the histone H3 acetylation profile in the presence of toxic substances in S. Cerevisiae.

Mentored by Pr. Frédéric Devaux.

2005

Research Assistant: Department of Cellular and Molecular Medicine, Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, Copenhagen, Denmark.

Subject: Characterisation of chromosomal breakpoints in Crohn’s disease patients.

Mentored Pr. Zeynep Tümer.

2004

Research Assistant: Genomics Platform, Institut Pasteur of Paris, France.

Subject : Molecular typing of Acinetobacter strains from the Pasteur Institute Collection.

Mentored by Dr. Christiane Bouchier.

2003

Research Assistant : Institute of Genetics & Microbiology, UMR8621, Université Paris XI - Orsay, France.

Subject : Function of the HAP5 gene in the yeast Kluyveromyces Lactis.

Mentored by Pr. Monique Bolotin-Fukuhara.

FELLOWSHIPS

2017: Marie Sklodowska-Curie action (MSCA) Postdoctoral fellowship. Chromatin and Splicing team, department of Genome Dynamics, Institut de Génétique Humaine, CNRS UMR9002, Université de Montpellier, France.

2016: ARC Postdoctoral fellowship. Chromatin and Splicing team, department of Genome Dynamics, Institut de Génétique Humaine, CNRS UMR9002, Université de Montpellier, France.

2009: ARC 4th year of PhD funding. Non-coding RNAs, Differentiation and Development group. Epigenetics and Cell Fate Unit, CNRS UMR7216, Université de Paris, France.

2006: PhD scholarship, French ministry of research and technology. Non-coding RNAs, Differentiation and Development group. Epigenetics and Cell Fate Unit, CNRS UMR7216, Université de Paris, France.

SUPERVISION OF GRADUATE STUDENTS AND POSTDOCTORAL FELLOWS

2022: - Postdoc: Bandana Kumari. Machine learning & gene regulation team. Co-supervised with William Ritchie. Institut de Génétique Humaine, Université de Montpellier, France.

  • PhD student : Marie-Sarah Cabrillac. Chromatin and Splicing group. Co-supervised with Reini Luco, Institut de Génétique Humaine, , Université de Montpellier, France.

  • M1 student: Nicolas Gaubert. Université de Rennes I, France.

2021: - PhD student : Marie-Sarah Cabrillac. Chromatin and Splicing group. Co-supervised with Reini Luco. Institut de Génétique Humaine, Université de Montpellier, France.

  • L3 student : Victor Perreaux. École Normale Supérieure of Paris, France.

2020: - M1 student : Soumya Bouchouika. Université de Montpellier, France.

  • M2 student : Katharina Arnold. Molecular Biosciences master’s program at the EMBL, Heidelberg, Germany.

2018: - M2 student: Samira Kemiha. Université de Montpellier, France.

TEACHING ACTIVITIES
2006-2009: Teaching Assistant. Cellular Biology. Université Paris VI - Pierre et Marie Curie, France.

ORGANISATION OF SCIENTIFIC MEETINGS

2017 – present: Organizer of the weekly IGH internal seminars. In person, remotely or hybrid. Between 40 and 70 attendees. Montpellier, France.

2018: co-organizer of Chromatin meets South. 12th & 13th of June. 120 participants. Genopolys, Montpellier, France.

INSTITUTIONAL RESPONSIBILITIES

2017 – present: Organizer of the IGH internal seminars, Montpellier, France.

2020 – present: Responsible of one of the IGH cell culture rooms, Montpellier, France.

2020 – present: member of the IGH Green committee, Montpellier, France.

COMMISSIONS OF TRUST

2019 – present: Evaluator of Marie Sklodowska-Curie Actions (MSCA) Postdoctoral fellowships applications. Europe.

MAJOR COLLABORATIONS

- William Ritchie. Topic: Identifications of the determinants responsible for consecutively retained introns. Machine learning & gene regulation team, Institut de Génétique Humaine, Université de Montpellier, France.

- Tom Sexton. Topic: Understanding the role of enhancer-promoter interactions during the epithelial-to-mesenchymal transition. Spatial organization of the genome group, Functional Genomics and Cancer department, IGBMC, Strasburg, France.

- Emmanuelle Charafe-Jauffret & Christophe Ginestier. Topic: Studying chromatin accessibility and gene expression in patient-derived xenografts of human metastatic breast cancer single-cells. Epithelial stem cells and Cancer group, CRCM, Marseille, France.

- Pengyi Yang. Topic: Bioinformatic analysis of single-cell ATAC-seq and RNA-seq. Computational Systems Biology group, Children's Medical Research Institute, Charles Perkins Centre, University of Sydney, Australia.

FUNDING

2023-2026 : ANR PRC

2021-2023 : Emergence Canceropôle Grand Sud-Ouest

2022 : SIRIC/NUMEV