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Mechanisms of gene regulation by transcription factors

We explore the transcription regulatory mechanisms that govern genome regulation at the interface of transcription factors, chromatin proteins and the transcription machinery, framing findings in developmental processes.

Gene regulation is central to cellular destiny and heavily relies on the activity of transcription factors. Little is known about how transcription regulatory complexes assemble, how they negotiate chromatin and what underlies their functional specificity and diversity. Our projects aim at exploring the transcription regulatory mechanisms to ultimately gain insights into genome regulation. We focus on Hox transcription factors, a family of homeodomain transcription factors with key functions in development, evolution and physio-pathological processes.

Work from the team has contributed to clarify the Hox specificity paradox, by identifying the Hox intrinsic protein sequences responsible for specificity, and by discovering novel modes of interactions with the PBC class specificity cofactors. We also identified physical and functional links with chromatin proteins, including PcG and Mediator complex proteins, as well as links with the transcription pausing factor M1BP, connecting Hox protein activity to chromatin modification and to the activity of the basal transcription machinery.

More recently, we uncovered a novel facet of Hox protein function, where Hox proteins act in a paralogue non-specific manner, a property that better suits the shared Hox biochemical properties. Our current research directions aim at investigating at the physiological level how Hox specific and non-specific functions relate to each other, by exploring Hox protein functions in two tissues, the larval fat body and adult muscle development. Work also aims at uncovering molecular principles of Hox generic functions, which have so far not been studied.

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Grienenberger Aurélie
PhD student, now Chief Busness Officer Eligo Bioscience
Merabet Samir
PhD student, now Group leader at IGFL, Lyon
Saadaoui Mehdi
PhD student, now CR CNRS at IBDM
Bruno Hudry
PhD student, now CR CNRS, Group leader at IBV, Nice
Miotto Benoit
PhD student, now Group leader at Institut Cochin, Paris
Nagraj Sambrani
PhD student, now freelance writer
Ankush Auradkar
PhD student, now postdoc at University of San Diego
Amel Zouaz
PhD student, now Research Tech at IBDM
Meiggie Macchi
PhD student, now Teacher in high school
Marwa Elrefaey
PhD student, now Medical Writer at VMLY&R International
Axelle Wilmerding
PhD student, now Post-doctoral fellow at IBMB, Barcelona
Marine Barthez
PhD student, now Post-doctoral fellow at University of California, Berkeley
Lucrezia Rinaldi
PhD student, now Post-doctoral fellow at Beth Israel Deaconess Medical Center/Harvard Medical School, USA

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Mechanisms of gene regulation by transcription factors

We explore the transcription regulatory mechanisms that govern genome regulation at the interface of transcription factors, chromatin proteins and the transcription machinery, framing findings in developmental processes.

The role of Hox in the development of Drosophila adult muscle development

The Drosophila life cycle comprises two mobile stages, the larval stage where the crawling movements enable larval feeding and the adult stage where flies can fly, jump and walk. Distinct sets of muscles, produced by two rounds of myogenesis are used during each stage, with larval muscles being produced during embryogenesis and the adult muscles during metamorphosis. In the embryonic somatic mesoderm, Hox gene expression has a spatially restricted pattern, where Scr is expressed in the first thoracic segment, T1, Antp in T2 and T3, Ubx in abdominal segments A1-A7, abd-A in A4-A8 and AbdB in A8-A9. Numerous studies have demonstrated a clear role for Hox genes in embryonic muscle patterning where Hox genes would confer a specific identity to the muscle precursors and account for segment-specific differences in the muscle pattern, through Hox-mediated regulation of muscle identity transcription factors (iTF).

The postembryonic development of the muscles of the adult fly has been the focus of much recent investigation of myogenesis since specific flight muscles of the fly (the indirect flight muscles, IFM) and appendicular myogenesis of the leg muscle manifest remarkable similarities to vertebrate myogenesis in their development and organisation. We are studying the role Hox, as well as other transcription factors play in the development of Drosophila adult musculature, focussing on two main sets of adult Drosophila musculature: the flight and leg muscles.

Transcriptional regulation of oxidative metabolism during Drosophila adult myogenesis

Mitochondria act as central metabolic hubs and their plasticity is essential to this function, where they rapidly adapt to changing environmental cues and metabolic alterations to meet the biogenetic demands of the cell. At the heart of mitochondrial metabolism lays oxidative phosphorylation (OXPHOS), a process that is fuelled by respiration and the electron transport chain (ETC). Nuclear genes that encode the vast majority of OXPHOS complex subunits are ubiquitously expressed from TATA-less promoters, a characteristic of “housekeeping genes” usually not subject to large amplitudes in gene expression. This has incorrectly conveyed the idea that transcriptional regulation is not key to plasticity in OXPHOS gene expression.
We, and others have shown that Drosophila M1BP is a sequence-specific RNA Polymerase II pausing factor that cooperates with other transcription factors, including Hox, to increase transcriptional output. We have recently shown that M1BP is an essential master transcriptional regulator of oxidative metabolism and are studying the gene regulatory network and changes in the chromatin landscape that are at the heart of transcriptional plasticity of OXPHOS gene expression in response to cellular needs. To this end, we use the Drosophila indirect flight muscle (IFM) as model since massive and selective increase in OXPHOS gene expression is observed during IFM development during pupation.

Metabolic control in the Drosophila larval fat body

We recently uncovered an unconventional Hox protein activity in the Drosophila fat body. In this tissue Hox proteins are neither differentially expressed, nor act in a paralog-specific manner to provide positional information. Instead, Hox proteins all provide a same and unique function, by timing the onset of developmental autophagy. Transcriptomic characterisation of Hox function in the fat body supports a Hox generic autophagy control, but also identifies a larger fraction of genes that appear specifically controlled by individual Hox proteins, many of which encode metabolic related genes. These recent findings open novel avenues to study Hox generic functions and how they relate to specific ones. In a broader perspective, they also provide the frame to interrogate the cellular links between developmental control and metabolism, and uncover the molecular bases for cellular specialisation of the fat body, a Drosophila liver/adipose like tissue, that despite its pleiotropic functions is seen as an homogenous entity. Ongoing work aims at addressing these physiological and mechanistic issues.

Molecular modalities of Hox protein mode of action

The importance of Hox proteins in development, evolution and physio-pathological processes is strongly established. Contrasting with this, very little is known about how Hox proteins operate as transcription factors. Our team has a longstanding interest in deciphering the intrinsic molecular support for Hox protein functions. Work focused on deciphering the modalities of Hox protein specificity, i.e. how proteins with a highly conserved DNA binding domain reach functional diversity, characterising the interface with the transcription machinery and chromatin.
Well-known for their specific functions in promoting morphological diversification during development and evolution Hox proteins also share common functions, which has long been overlooked and only recently highlighted. We recently explored how Drosophila Ubx and AbdA, two phylogenetically strongly related proteins Hox proteins, perform identical functions, with the intuitive assumption that it would rely on conserved Ubx/AbdA protein sequences. Surprisingly we found that protein motifs conserved in Ubx and AbdA are distinctly used for shared genomic targeting and multiple developmental functions, highlighting distinct molecular strategies for shared in vivo functions. These results challenge the view that conserved protein motifs generally serve identical functions, and suggest that not only motif presence but also motif usage is central to changes/evolution of protein activity. Ongoing work aims at elucidating how Intrinsically disordered protein region (IDR), containing Short Linear Motifs (SLiMs), defines the mode of motif usage.
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