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Regulation of gene expression during development

Mounia Lagha

Research projects

A fundamental question in biology is how cellular processes are so reproducible despite the inherent variations in the chemical reactions governing them. During the development of a multicellular organism, precise control of gene expression allows the reproducible establishment of patterns that will lead to the formation of tissues and organs at the right time in the right place. While numerous studies have established how the spatial information is achieved and integrated by enhancers, less is known concerning the temporal features of transcriptional control. This is particularly true for transcriptional coordination, which refers to the inter-nuclear synchrony of gene activation and to the homogenous distribution of mRNAs across a field of coordinately developing cells. Our goal is to integrate the dynamic aspects of transcription to understand how a precise temporal coordination in gene expression leads to accurate cell fate decisions during development.

We mainly study early Drosophila development: the first 4 hours of embryogenesis.

The approach is highly integrative with techniques ranging from classical genetics and molecular biology to whole-genome profiling and state of the art live imaging microscopy. Image quantification and mathematical modeling are important aspects of our research.

 

Transcription activation in living embryos

 

Figure 1 : Imaging transcription in living embryos

Figure 2 : Image analysis pipeline

Imaging translation in living embryos

 

Figure 3: Principle of the SunTag approach

 

Example of specific projects/recent achievements:
Examine the effects of promoter sequences and enhancer priming on transcriptional coordination
Figure 4 : The INR promoter motif leads to an extra regulatory checkpoint associated with stochastic pausing, imposed on only a subset of polymerases. Pimmett*, Dejean* et al., in press at Nature Communications.

 

How do promoters influence transcriptional bursts? Using quantitative live imaging, genetic manipulation and mathematical modeling, we can decode how core promoter motifs regulate key rate-limiting steps of transcription in the early Drosophila embryo. Applying a novel machine learning approach, we discovered TATA box-driven promoters can be recapitulated by a simple two state model with an inactive OFF and permissive ON from which Pol II initiates transcription. Loss of the TATA motif reduces the ON state duration. The Initiator (INR) promoter motif, in contrast, is associated with a three state model consisting of a permissive ON, OFF1 (on the order of seconds) and OFF2 (on the order of minutes). This long, infrequent OFF2 state is associated with Pol II pausing, but under a model where only a subset of polymerases are stably paused. Our goal is to understand the genetic and molecular mechanisms underlying promoter state transitions during the maternal-to-zygotic transition.

 

 

Analyze the inheritance of transcriptional states from mother to daughter cells and identify the bookmarking mechanisms at play

 

Live imaging of transcription allows us to record, for the first time, the inheritance of active transcriptional states (memory) from mother to daughter cells during Drosophila embryogenesis. Here, memory is related to the kinetics of gene de novo re-activation during mitotic exit (transcriptional foci) and not to the inheritance of accumulated cytoplasmic mRNAs.

Our objective is to document the existence of transcriptional memory in the early embryo and understand the function and mechanisms regulating this phenomenon.

Video 2 & Figure 5: Visualization of Memory
Figure 6 : Acetyl mark in mitosis

 

Quantifying translation in space and time during development

During development, precise control of gene expression allows the reproducible establishment of patterns, leading to the formation of organs at the right time and place.

The establishment of developmental patterns has been primarily studied at the transcriptional level. In comparison, the fate of these transcripts received little attention.

Dufourt*, Bellec* et al deployed the SunTag labeling method to image the dynamics of translation of individual mRNA molecules in living Drosophila embryos. This led to the discovery of translation factories and unmasked important heterogeneities in the efficiency of translation between identical mRNAs, demonstrating a novel layer of fine-tuning of gene expression.

Dufourt J, Bellec M, Trullo A, Dejean M, De Rossi S, Favard C, Lagha M. 
Science. 2021 Apr 29:eabc3483. doi: 10.1126/science.abc3483. Online ahead of print.
PMID: 33927056

Members

Team leader

Mounia LAGHA

Chercheur DR2

+33 (0)4 34 35 96 50

104

Maelle BELLEC

Doctorant

+33 (0)4 34 35 96 50

Maria DOUAIHY

Doctorant

+33 (0)4 34 35 96 51

Jeremy DUFOURT

CRCN

+33 (0)4 34 35 96 53

Louise MAILLARD

Doctorant

+33 (0)4 34 35 96 50

104

Virginia PIMMETT

Post-Doc

+33 (0)4 34 35 96 53

104

Antonio TRULLO

IR-Recherche

+33 (0)4 34 35 96 50

Morgane VERBRUGGHE

IE-Recherche

+33 (0)4 34 35 96 53

104

Previous lab members

Matthieu Dejean / Research Assistant

Marion Goussard /  Research Assistant

Maelys Gicquel / Research Assistant

Carola Fernandez / PhD Student

Jennifer Hunter / Post-Doc

Yayoi Wada / trainee

Elisa Atger / trainee

Rachida el Youssfi / trainee

Matilde Gauchier / trainee

Matilde Montovani / trainee

Louis Redonnet / trainee

Jonathan Lapine / trainee

Quentin Dessables / trainee

Yasmine Hadj-Messaoud / trainee

Matilde Mantovani / trainee

Yayoi Wada /  trainee

Quantin Dessables /  trainee

Mathilde Gauchier /  trainee

Louis Redonnet / trainee

Rachida el Youssfi / trainee

Elisa Atger / trainee

Hoa Vinh Le /  trainee

Saida Nait Amer / trainee

Lucas Makinen / trainee

Basile Poutier / trainee

Lucas Morales / trainee

Jorge Lazaro / trainee

Olivier Messina / trainee

Heloise Faure-Gautron / trainee

Selected Publications

More information

Funding

2020              

ANR MemoRNP (with F.Besse)

2020             

CNRS-Chicago Prime80 (with J.Reinitz and O.Radulescu)

2020             

LabMuse PhD network (3 PhD fellowships with E.Bertrand, S.Chambeyron and O.Radulescu)

2018

FRM fellowship to support M.Bellec PhD under my supervision

2015              

FRM grant to support the salary of a research engineer

2015              

ERC starting grant, SynDev

 

Interactions
In Montpellier

O.Radulescu and L.Ciandrini (Univ.Montpellier) : mathematical modeling

National and international

M.Harrison (University of Wisconsin Madison, USA): Role of Zelda

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Team Overview
Model organism studied
Drosophila Melanogaster
Biological process
Gene expression, transcriptional dynamics
Biological techniques
Quantitative live imaging, genetics