Unraveling HSF-dependent stress response pathway dysregulation in neurodevelopmental disorders: new therapeutic avenues

Neurodevelopmental disorders (NDDs) affect 10% of children, causing lifelong cognitive and behavioral challenges. The clinical variability of NDDs complicates the search for effective treatments. Our project targets a common feature across NDDs: disruption of stress response pathways, specifically involving Heat Shock Factors (HSFs). HSF2, which regulates proteostasis during stress, also plays a key role in brain development under normal conditions. Using two patient-derived iPSC models of NDDs—both exhibiting HSF2 dysregulation—and their isogenic models with restored HSF2, we aim to pinpoint the specific role of the HSF pathway in NDDs. Through advanced single-cell analyses applied to cerebral organoids derived from these models, we will identify HSF-dependent genes, pathways, and cell populations. These discoveries will be validated through independent approaches and will serve as a “readout” for future drug screening.

The team has extensive expertise in the CRISPR system, cell culture, and organoid formation, supported by collaboration with the ENscore platform, as well as bioinformatics support through EDC platforms, including BiBs and WISCI (10X Genomics).

The full description of the project is on the website https://dim-cbrains.fr/fr/phd-program/dim-cbrains ( see below)

Public funding alone (i.e. government, region, European, international organization research grant)

his doctoral program, conducted by DIMC Brain, follows a rigorous selection process managed by the organization. Candidates will be evaluated based on their academic background, research experience, and alignment with the program's objectives. The selection process will also include interviews and a review of proposed research projects to ensure the best fit for the program’s goals.

UMR7216 - Epigenetic and Cell Destinity

The “Epigenetic and Cell Destinity” unit is a multidisciplinary research center founded in 2009 and located on the Grands Moulins campus of Paris Cité University.

Directed by Dr. V. MEZGER and Dr. C. ROUGEULLE, the unit brings together a network of teams with complementary expertise in molecular epigenetics, including DNA methylation, histone variants and modifications, and non-coding RNAs. Their research focuses on the role of these mechanisms in development, differentiation processes, and their contributions to pathological conditions.

The unit’s research activities are supported by a range of state-of-the-art technical platforms and facilities, as well as comprehensive support services across various fields.

Doctorat de science

France

Université Paris CIté

Bio Sorbonne Paris Cité (BIOSPC)

Expected involvement of the student in the project and desired skills

The candidate will develop the NDD model (Angelman-like syndrome, AGS-L) by generating patient human cortical organoids (hCOs) and HSF2-rescued patient hCOs (done by genome editing), then conduct a single cell multi-omics comparative analysis of HSF2-rescued and patient hCOs at two developmental stages. Finally, he will validate the defective molecular pathways identified in hCOs, focusing on stress and adhesion related pathways. Combining results from the RSTS model and the established AGS-L model will shed light on the core defective pathways dependent on HSF2.

 

Expected competences:

1.              Educational Background:

Degree in neuroscience, cell biology, or a related field, with relevant coursework in neurobiology.

2.              Technical Skills:

Proficiency in 2D and eventually 3D cell culture

Experience with single-cell RNA sequencing (scRNA-seq) and associated data analysis.

3.              Attention to Detail and Organization: Meticulous approach to experiments, strong organizational skills for managing multiple projects, and maintaining detailed records.

4.              Bioinformatics Knowledge: Basic understanding of bioinformatics tools for analyzing genomic data.

5.              Collaboration Skills: Ability to work effectively in a team and communicate findings clearly.

6.              Passion for Research: Enthusiasm for neuroscience and a commitment to advancing the field.