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You are here: Home / Teams / Regulation of Genome Architecture and Dynamics of Splicing (ReGArDS) - D. Auboeuf and C. Bourgeois / Chromatin topology, transcription, and alternative splicing during inflammatory and oncogenic processes - Franck Mortreux

Chromatin topology, transcription, and alternative splicing during inflammatory and oncogenic processes - Franck Mortreux

 Chromatin topology, transcription, and alternative splicing during inflammatory and oncogenic processes. 

PI : Franck Mortreux 

Regulatory mechanisms of splicing have long been considered as post-transcriptional events depending exclusively on the abundance of splicing factors and their post-translational regulation. However, it is now well established that these processes are tightly coupled to transcription for the vast majority of human genes. The parameters that influence splicing decisions are multiple, including chromatin remodeling and RNAPII elongation kinetics, but also the structure of promoters, enhancers, and the nature of the transcription factors (and/or cofactors) that are recruited to them. 

Our work focuses on the molecular mechanisms underlying chromatin topology, transcription, and alternative splicing during inflammatory and oncogenic processes. Our study model is the viral oncogenic infection by HTLV-1 (Human T-cell leukemia Virus type 1) which is the causative agent of an aggressive T-CD4+ haematological malignancy (Adult T-cell Leukaemia/Lymphoma (ATLL)) and various inflammatory diseases in 2-5% of infected individuals. We have recently discovered that, in addition to the numerous transcriptional alterations that accompany infection, alterations in alternative splicing of cellular transcripts are also common, particularly in the ATLL cells. Interestingly, these changes affect distinct functional pathways than those deregulated at the transcriptional level. In particular, these include cell adhesion processes, which might contribute to the extravasion of infected cells to other anatomical compartments, as well as other functional pathways likely involved in the pathophysiology of the infection. 

The viral oncogenes Tax and HBZ are well known to act as transcriptional co-factors. They disrupt the activity of many critical regulators such as NF-kB, AP-1, and SMAD and affect in turn the regulation of cell cycle, genome integrity and immune response. Our recent results indicate that TAX and HBZ also generate numerous splicing modifications by intervening in the transcription/splicing coupling mechanisms. We are using the properties of these viral factors to dissect the mechanisms that link the regulation of alternative splicing to chromatin remodelling and the spatio-temporal organisation of genes. 

Our studies combine experimental and bioinformatic approaches. In particular, we use RNA-seq, qChiP, ChiP-seq, Cut&Run, 3C (Chromosome Conformation Capture), 4C and Hi-C methods for assessing transcriptomic and chromatin changes. We have also developed TALE, CRISPR/Cas9, CRISPR-dCas9-KRAB, CRISPR-dCas9-VPR, CLOuD9 tools to carry out targeted modifications to DNA and chromatin. 

Three axes are developed: 


Role of p65/RELA and the RNA helicase DDX17 in defining splice targets during activation of the NF-kB pathway by TAX. Lamya Ben Ameur (post-doc)


Here we address the role of TAX in disruption of alternative splicing regulation. Our data show that these novel properties of the viral oncogene operate independently of its effects on gene expression. In particular, our results have evidenced regulatory mechanisms where intragenic recruitment of NF-kB RELA lead to anchor the splicing factor DDX17 to the chromatin and to regulate the target exon thanks to its helicase activity. Interestingly, this mechanism was also observed when the NF-kB pathway is activated independently of TAX. These data thus reveal a physiological mechanism where NF-kB provides splicing target definition, which would likely be exacerbated by TAX through its constitutive effects on NF-kB activation.. 

Owing to these new data, we are now interested in the functional impacts of such NF-kB-induced splicing regulation in inflammation and cell transformation, more particularly by exploring the distinct roles of canonical and non-canonical NF-kB signalling pathways.


Spatio-temporal coordination of alternative splicing and gene transcription upon NF-kB activation: role of TAX .  Paul Marie (PhD)


Physiological expression of human genes requires tight coordination of gene transcription. It has been proposed that spatiotemporal coordination takes place in nuclear foci, also called transcription factories, which are composed of several RNAPIIs, other factors essential for transcriptional initiation and elongation, and post-transcriptional regulation. It has been proposed that one of the primary functions of transcription factories is to cluster genes that are co-regulated by same transcription factor. For example, in response to TNF-α, 3C (Chromosome Conformation Capture) and RNA-FISH approaches have identified the formation of NF-kB factories where transcription of responsive genes is coordinated upon activation of the NF-kB pathway. NF-kB factors and DDX5/17 RNA helicases have also been directly implicated in DNA loop formation during transcriptional processes. The viral oncogene TAX is also known to form nuclear structures (TAX speckles) enriched in NF-kB factors, hyperphosphorylated RNAPII and splicing factors. In this context, our objectives are to address the effects of TAX on chromatin topology, gene clustering and their transcriptional and post-transcriptional regulation.


Regulation of retrograde splicing and circular RNA biogenesis: role of HBZ Julien Ladet (PhD)


Circular RNAs (CRNAs) are a large class of RNAs that are frequently deregulated in tumours. Their biological functions are diverse, including sequestration of microRNAs (miRNA sponges), transcriptional regulation, and synthesis of specific peptides/proteins. The regulation of circRNA expression involves back splicing processes, which is still poorly understood. Our recent analysis of circRNA abundance in ATLs revealed massive deregulation of constitutive circRNAs (commonly expressed in donor CD4+ cells), some of them being already described as tumour suppressors. Our preliminary data reveal that the viral oncogene HBZ, so far defined as a transcriptional regulator, interacts with many splicing regulators and other actors in circRNA biogenesis. Our hypothesis is that circRNA deregulation evidenced in ATLs may result from interactions between HBZ and RNA binding proteins involved in alternative splicing and DNA topology. In this setting, our objective is to decipher the molecular mechanisms that link chromatin conformation and regulation of alternative splicing to circRNA biogenesis. 


Recent publications : 

- Antony Ceraulo, Hélène Lapillonne, Meyling H Cheok, Claude Preudhomme, Hervé Dombret, Christine Terré, Juliette Lambert, Guy Leverger, Yves Bertrand, Franck Mortreux*, Eric Wattel*. Prognostic impact of ABCA3 expression in adult and pediatric acute myeloid leukemia: an ALFA-ELAM02 joint study. Blood Adv. 2022 Jan 10. doi: 10.1182/bloodadvances.2021006040.

- Ameur LB, Marie P, Thenoz M, Giraud G, Combe E, Claude JB, Lemaire S, Fontrodona N, Polveche H, Bastien M, Gessain A, Wattel E, Bourgeois CF, Auboeuf D, Mortreux F. Intragenic recruitment of NF-κB drives splicing modifications upon activation by the oncogene Tax of HTLV-1. Nat Commun. 2020 Jun 16;11(1):3045. doi: 10.1038/s41467-020-16853-x.

- Ladet J, Mortreux F. Circular RNA, actors and biomarkers of cancers. Med Sci (Paris). 2020 Oct;36(10):935-938. doi: 10.1051/medsci/2020165.

- Mohamed, A. M., Balsat, M., Koering, C., Maucort-Boulch, D., Boissel, N., Payen-Gay, L., Cheok, M., Mortada, H., Auboeuf, D., Pinatel, C., El-Hamri, M., Tigaud, I., Hayette, S., Dumontet, C., Cros, E., Flandrin-Gresta, P., Nibourel, O., Preudhomme, C., Thomas, X., Nicolini, F. E., Solly, F., Guyotat, D., Campos, L., Michallet, M., Ceraulo, A., Mortreux, F., and Wattel, E. (2017) TET2 exon 2 skipping is an independent favorable prognostic factor for cytogenetically normal acute myelogenous leukemia (AML): TET2 exon 2 skipping in AML. Leuk Res 56, 21-28

- Mohamed, A. M., Balsat, M., Thenoz, M., Koering, C., Payen-Gay, L., Cheok, M., Mortada, H., Auboeuf, D., Pinatel, C., El-Hamri, M., Dumontet, C., Cros, E., Flandrin-Gresta, P., Nibourel, O., Preudhomme, C., Michallet, M., Thomas, X., Nicolini, F., Solly, F., Guyotat, D., Campos, L., Wattel, E., and Mortreux, F. (2016) Oncogene- and drug resistance-associated alternative exon usage in acute myeloid leukemia (AML). Oncotarget 7, 2889-2909

- Thenoz, M., Vernin, C., Mortada, H., Karam, M., Pinatel, C., Gessain, A., Webb, T. R., Auboeuf, D., Wattel, E., and Mortreux, F. (2014) HTLV-1-infected CD4+ T-cells display alternative exon usages that culminate in adult T-cell leukemia. Retrovirology 11, 119

- Vernin, C., Thenoz, M., Pinatel, C., Gessain, A., Gout, O., Delfau-Larue, M. H., Nazaret, N., Legras-Lachuer, C., Wattel, E., and Mortreux, F. (2014) HTLV-1 bZIP factor HBZ promotes cell proliferation and genetic instability by activating OncomiRs. Cancer research 74, 6082-6093


Funds :



2022-2026       ANR INFLASPLICE (ANR-21-CE15-0036-02)

2016-2020       ANR CHROTOPAS (ANR16 CE12-0009-01)

2011-2015       ANR EPIVIR



Main collaborations

Thomas SEXTON (IGBMC, Illkirch/Strasbourg, France)

Hélène Dutartre and Chloé Journo (CIRI, Lyon, France)

Jean-Claude Twizere (GIGA, Liege, Belgium)

Anne Van den Broeke (GIGA, Liege, Belgium)

Greta Forlani and Roberto Accolla (Università degli Studi dell'Insubria - Italia)

Eric Wattel (Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France)



Former PhD students 


- Antony Ceraulo (2017-2021), MD/PhD Pediatrician HOPe, CRCL, Lyon

- Lamya Ben Ameur (2015-2019), doctoral fellowship from the Ligue contre le Cancer

- Aminetou Mint Mohamed* (2012-2016), doctoral fellowship from Mauritania

- Morgan Thénoz (2010-2014), doctoral fellowship EDISS

- Celine Vernin (2009-2013), doctoral fellowship EDISS

- Maroun Karam (2008-2012), doctoral fellowship FRM

- Linda Zane* (2006-2009), doctoral fellowship from la Ligue contre le Cancer

- Valerie Capraro* (2005-2008),  doctoral fellowship from EDISS

- Carole Pomier (2004-2008), doctoral fellowship from la Ligue contre le Cancer