Team
Team manager: Egloff sylvain
Presentation
Unlike a simple ‘on-off’ switch, transcription by RNA polymerase II (RNAPII) is a highly dynamic, multistep process in which each phase plays a critical role in shaping gene expression. Our research aims to uncover how RNAPII dynamics influence transcriptional output, with a particular focus on two key regulatory checkpoints: promoter-proximal pausing and elongation speed. We explore how diverse molecular players – including cyclin-dependent kinases (CDKs), phosphatases, non-coding RNAs, chromatin remodelers, and transcription factors – coordinate RNAPII progression along genes.
A major focus of our work is to understand how these regulatory mechanisms adapt in response to environmental cues and during developmental transitions, such as stem cell differentiation. We are also investigating how perturbations in RNAPII dynamics contribute to human diseases, especially cancer and neurodevelopmental disorders. To address these questions, we leverage state-of-the-art transcriptomics technologies that provide deep insights into transcriptional and co-transcriptional regulation.
Project 1
Promoter-proximal pausing is a pivotal regulatory step in the transcription of protein-coding genes by RNA polymerase II (RNAPII). The release of paused RNAPII into productive elongation is primarily driven by positive transcription elongation factor b (P-TEFb), a complex composed of the CDK9 kinase and Cyclin T1 that is essential for the synthesis of full-length messenger RNAs. P-TEFb activity is tightly controlled by the 7SK small nuclear RNA (7SK snRNA), which, along with MePCE, LARP7, and HEXIM1, forms a large, kinase-inactive complex known as the 7SK/P-TEFb snRNP. This ribonucleoprotein complex regulates the availability of active P-TEFb by sequestering or releasing it in response to the cell’s transcriptional demands, making it one of the most potent regulators of RNAPII pausing in human cells. For instance, during cellular stress, P-TEFb is rapidly released from the 7SK snRNP, triggering widespread release of paused RNAPII and enabling rapid reprogramming of gene expression. This dynamic regulation suggests that the 7SK snRNP plays a crucial role in timing key transcriptional transitions – not only during stress responses, but also throughout development and tumorigenesis. Importantly, impaired association between P-TEFb and the 7SK snRNP has been linked to malignant transformation in cultured cells and is associated with a range of human diseases, including cancer, cardiac hypertrophy, neurodevelopmental disorders, viral infections, and inflammatory and autoimmune conditions. Understanding the multifaceted regulatory functions of the 7SK snRNP across physiological and pathological contexts is a central goal of our research.
Project 2
Transcription by RNA pol II has been extensively studied, yet one critical aspect – the elongation speed of RNA Pol II, or the rate at which it moves along DNA to synthesize RNA – remains relatively poorly characterized. This speed determines the number of nucleotides added to the growing RNA strand per unit of time and is known to be highly dynamic and tightly regulated, both within individual genes and between different genes. Importantly, transcription speed is a major determinant of RNA identity. Studies using RNA Pol II mutants with altered elongation rates have demonstrated that transcription speed can influence key co-transcriptional processes, including splicing, circular RNA production, alternative polyadenylation, and transcription termination. Our research aims to uncover how the elongation speed of RNA Pol II is locally modulated during physiological and pathological processes, including cellular transformation. By applying transcriptomic approaches, we aim to correlate changes in transcriptional velocity with alterations in RNA composition and identity. This will help us understand how modulation of RNA Pol II speed contributes to transcriptome reprogramming during cell fate transitions and cancer progression. In parallel, we are using CRISPR library screens in combination with reporter systems to identify novel regulators that locally modulate RNA Pol II elongation speed. Once identified, these factors are functionally characterized to reveal their roles in transcriptional regulation and their potential involvement in oncogenesis and other critical biological processes.
– Yang Y, Liu S, Egloff S, Eichhorn CD, Hadjian T, Zhen J, Kiss T, Zhou ZH, Feigon J. (2022) Structural basis of RNA conformational switching in the noncoding 7SK core RNP. Mol Cell. doi: 10.1016/j.molcel.2022.03.001.
– Studniarek C, Tellier M, Martin P, Murphy S, Kiss T, Egloff S. (2021) The 7SK/P-TEFb snRNP controls ultraviolet radiation-induced transcriptional reprogramming. Cell Reports. doi: 10.1016/j.celrep.2021.108965.
– Muniz L, Lazorthes S, Delmas M, Ouvrard J, Aguirrebengoa M, Trouche D, Nicolas E. (2021) Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced senescence. RNA Biol. doi: 10.1080/15476286.2020.1812910.
– Egloff S. (2021) CDK9 keeps RNA polymerase II on track. Cell Mol Life Sci. doi: 10.1007/s00018-021-03878-8.
– Studniarek C, Egloff S, Murphy S. (2021) Non-coding RNAs set the stage for RNA polymerase II transcription. Trends Genet. doi: 10.1016/j.tig.2020.09.013.
– Muniz L, Nicolas E, Trouche D. (2021) RNA polymerase II speed: a key player in controlling and adapting transcriptome composition. EMBO J. doi: 10.15252/embj.2020105740.
– Egloff S, Studniarek C, Kiss T. (2018) 7SK small nuclear RNA, a multifunctional transcriptional regulatory RNA with gene-specific features. Transcription. doi: 10.1080/21541264.2017.1344346.
– Egloff S, Vitali P, Tellier M, Raffel R, Murphy S, Kiss T. (2017) The 7SK snRNP associates with the little elongation complex to promote snRNA gene expression. EMBO J. doi: 10.15252/embj.201695740.
– Muniz L, Deb MK, Aguirrebengoa M, Lazorthes S, Trouche D, Nicolas E. (2017) Control of gene expression in senescence through transcriptional read-through of convergent protein-coding genes. Cell Reports. doi: 10.1016/j.celrep.2017.11.006.
Affiliation
