Our Research activities

Our group studies the molecular mechanisms controlling gene expression at the interface between transcription, chromatin and RNA metabolism, with a particular interest in the mechanisms underlying the establishment, maintenance and reactivation of HIV-1 latency. Our previous work revealed that the HUSH complex, composed of TASOR, MPP8 and PPHLN-1, associates with nascent RNA produced from its target genes. We showed that HUSH can recruit RNA degradation machineries associated with the nuclear RNA exosome, including CCR4-NOT and PAXT, to selected genomic targets. At the HIV-1 provirus, this mechanism promotes the degradation of newly synthesised viral RNA and limits the continuation of productive transcription, thereby contributing to the transcriptional silencing of the provirus. These findings were initially reported in Matkovic et al., bioRxiv (2020) and subsequently published in Nature Communications (2022). These findings uncovered a mechanism of gene repression in which the fate of nascent RNA is directly coupled to transcriptional control. Rather than acting only through the establishment of a repressive chromatin environment, HUSH is therefore able to act co-transcriptionally, linking RNA polymerase II-associated transcription with nuclear RNA surveillance and degradation. This work highlighted an intimate connection between nascent RNA metabolism and epigenetic gene repression in mammalian cells. Building on these observations, we are now trying to understand how HIV-1 RNAs and cellular non-coding RNAs contribute to the organisation and recruitment of macromolecular complexes that control proviral expression. In particular, we are interested in how cellular factors associated with chromatin, RNA polymerase II and nascent RNA cooperate to recognise and repress the provirus and to promote its transition towards a transcriptionally silent state.

An important part of our research is focused on mapping the molecular interactions occurring directly at the HIV-1 provirus, with the aim of identifying the host proteins and complexes involved in the establishment and maintenance of latency. By characterising the molecular environment surrounding the provirus, we seek to define which factors associate with viral chromatin and nascent viral RNA at different stages of latency, and how these interactions evolve over time. We consider the provirus as a dynamic molecular platform on which factors controlling transcription, chromatin organisation, epigenetic modifications and RNA fate progressively assemble. One of our main objectives is to understand how these different layers of regulation are coordinated, from the early events following viral integration to the establishment and long-term maintenance of a transcriptionally repressed state. Ultimately, we aim to identify the host factors and molecular pathways that determine the transcriptional fate of the HIV-1 provirus, and to understand why some infected cells efficiently establish and maintain a latent viral reservoir whereas others remain transcriptionally active.

Beyond HIV-1, this work also contributes to a broader understanding of how human cells coordinate transcription, chromatin organisation and RNA metabolism to achieve stable and long-term regulation of gene expression.

Our Expertise and approaches

We use complementary cellular models of HIV-1 infection and latency to investigate the molecular mechanisms that control proviral expression. Our work combines molecular and cellular biology, biochemistry, functional genomics and epigenomics to characterise the interactions between viral and host factors, RNA polymerase II, RNA and chromatin.

We apply a range of high-throughput and imaging-based approaches, including CUT&RUN, CUT&Tag, ChIP-seq, ATAC-seq, transcriptomic analyses, Nuclear Run-On (NRO) assays and single-molecule imaging. Together, these techniques allow us to map protein–chromatin interactions, profile histone modifications, measure chromatin accessibility, assess transcriptional activity and visualise molecular events at the single-molecule level. By integrating these complementary approaches, we aim to define how transcriptional, epigenetic and RNA-processing mechanisms are coordinated at the HIV-1 provirus and across the cellular genome.

By integrating biochemical, molecular and genome-wide approaches with proviral interaction mapping, we aim to reconstruct the molecular events leading to the establishment and maintenance of HIV-1 latency and to identify the cellular networks responsible for the long-term repression of the provirus.

Internal:
Florence MARGOTTIN-GOGUET
Véronique AVETTAND-FENOEL

Local:
-Stéphane EMILIANI - Institut Cochin
-Catherine LAVAZEC & Frédérique VERDIER- Institut Cochin

National:
-Gael CRISTOFARI - IRCAN Nice

International:
-Maike HANSEN - Radbud University - NED

Argonaute 1 contributes to the transcriptional silencing of HIV-1.

Goudey S, Said MA, Desforges J, Marie S, Morel M, Berlioz-Torrent C,
Margottin-Goguet F, Emiliani S, Matkovic R✉, Gallois-Montbrun S✉.
J Biol Chem. 2025 Aug 19:110612. doi: 10.1016/j.jbc.2025.110612.  (✉: co-corresponding)

Link to Article

Deciphering lentiviral Vpr/Vpx determinants required for HUSH and SAMHD1 antagonism highlights the molecular plasticity of these evolutionary conflicts.
Larrous P, Garnier C, Morel M, Martin MM, Zarrouk K, Maesen S, Matkovic R, Cimarelli A, Etienne L, Margottin-Goguet F.
J Virol. 2025 May 20;99(5):e0019825. doi: 10.1128/jvi.00198-25.

Link to Article

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV.
Matkovic R✉, Morel M, Lanciano S, Larrous P, Martin B, Bejjani F, Vauthier V, Hansen MMK, Emiliani S, Cristofari G, Gallois-Montbrun S, Margottin-Goguet F✉.
Nat Commun. 2022 Jan 10;13(1):66. doi: 10.1038/s41467-021-27650-5. (✉: co-corresponding)

Link to Article

HUSH-mediated HIV silencing is independent of TASOR phosphorylation on threonine 819.
Vauthier V, Lasserre A, Morel M, Versapuech M, Berlioz-Torrent C, Zamborlini A, Margottin-Goguet F✉, Matkovic R✉. Retrovirology. 2022 Oct 29;19(1):23. doi: 10.1186/s12977-022-00610-7 (✉ : co-corresponding)

Link to Article

Binding to DCAF1 distinguishes TASOR and SAMHD1 degradation by HIV-2 Vpx.
Martin MM*, Matkovic R*, Larrous P, Morel M, Lasserre A, Vauthier V, Margottin-Goguet F. PLoS Pathogens 2021 Oct 26;17(10):e1009609. doi: 10.1371/journal.ppat.1009609. (*: co-first)

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HIV-2/SIV viral protein X counteracts HUSH repressor complex.
Chougui G, Munir-Matloob S, Matkovic R, Martin MM, Morel M, Lahouassa H, Leduc M, Ramirez BC, Etienne L, Margottin-Goguet F. Nat Microbiol. 2018 Aug;3(8):891-897. doi: 10.1038/s41564-018-0179-6. 

Link to Article