I am currently part of the HAMMER Lab at the University of Michigan
Research Overview
SCIENTIFIC INTEREST
​
Glucocorticoids, such as cortisol (in humans) and corticosterone (in rodents), are cholesterol-derived hormones widely known and essential for maintaining glucose homeostasis, modulating immune response, and orchestrating circadian rhythm.
​
However, imbalance in their production is associated with diabetes, susceptibility to infections, cognitive dysfunction, elevated cardiometabolic morbidity and increased mortality. Thus, there is a critical need to identify novel regulators of adrenal function to serve as therapeutic targets.
​
A unique population of glucocorticoid-producing cells reside within a circumferential zone in the adrenal glands, localized on top of the kidney. This essential endocrine cell subtype constitutes the so-called zona fasciculata (zF) and is a crucial component of the Hypothalamo-Pituitary-Adrenal Axis (HPA), a complex neuroendocrine system that maintains metabolic homeostasis. In order to support the development of effective therapies, my long-term goal is to identify the molecular pathways crucial for glucocorticoid-producing cells.
​
My broad research interests are:
1) Elucidating the molecular mechanisms regulating the adrenal gland differentiation and its endocrine function
2) Combining the use of transgenic mouse models with single cell approaches to identify cell type specific disease mechanisms.​​​
​
STRATEGY
​
I use in vivo mouse models, single cell RNAsequencing, CUT&Tag for DNA binding profiling of transcription factor and histology techniques (RNAscope and Immunohistochemistry)
​
Fundings
Past Projects
University of Clermont Ferrand, France
The core of my doctoral research aimed to understand the origin of adrenal lesions in Carney Complex, a rare genetic disease that affects organ homeostasis in both connective and endocrine tissues. To address this question, we engineered several mouse models of Carney Complex targeting Prkar1a, the major gene affected in human patients which encodes the PKA regulatory subunit. This work conclusively demonstrated that these adrenal lesions arise in the postnatal adrenal cortex rather than from the fetal organ. Moreover, it highlighted the role of PKA signaling in the developmental process of adrenarche – a pubertal milestone driven by the adrenal cortex but poorly understood due to the lack of available animal models. An additional work built upon these studies highlighted the role of PKA signaling in controlling the process of SUMOylation in adrenocortical cells. By combining additional mouse models, in vitro pharmacological approaches, and endocrine manipulation, our experiments ultimately led us to discover that SUMOylation patterns are altered in adrenal lesions of Carney Complex patients.
These results led to two first-author publications (Dumontet et al., 2018. JCI Insight, Dumontet et al., 2019, FASEB) and the mouse models we developed will continue to provide valuable insight for translational research.
University of Michigan, USA
During my postdoctoral studies, I combined single cell technology and newly developed mouse models to uncover transcriptional programs participating in adrenal differentiation. I identified the homeodomain protein, HHEX, as the top enriched transcription factor in glucocorticoid-producing cells, called fasciculata cells. However, its role in adrenal homeostasis was unknown. To gain insights into HHEX contribution to adrenal function, I generated adrenal-specific Hhex knockout mouse models and observed that Hhex-deficient mice exhibited a profound glucocorticoid deficiency at baseline. By combining a series of experiment profiling Hhex DNA-binding, RNA sequencing and histology examination of Hhex-deficient adrenals, I provide evidence that HHEX orchestrates the function of the fasciculata cells to promote chronic stress adaptation and protect lipid droplet integrity in male mice (Dumontet et al., under revisions Nature Communications).