IRCM Researchers

The pituitary as model to understand development and disease
The long term endeavours have been to understand genetic and epigenetic mechanisms controlling gene expression, cell fate specification (cell identity) and organ development. The reasearch team primarily use the pituitary gland as model for these studies as it represents a simple organ constituted of six different cell types, each dedicated to production of a different hormone (Drouin J 2010 Pituitary Development. In: Melmed S (ed) The Pituitary 3rd Ed. Elsevier-Academic Press,3-19/ 4th Ed. 2017). The work has focused in particular on the pro- preproopiomelanocortin (POMC) gene that encodes the hormones ACTH, the melanotropins and endorphins. Dysfunction of these pituitary cells results in debilitating hormone deficiencies or overproduction. Discoveries of basic mechanisms of pituitary function have led to the identification of novel syndromes, provided diagnostic tools and opened new therapeutic approaches.

Tri-dimensional tissue organization
The advent of powerful tissue imaging technologies led the team members to collaborate with colleagues in Montpellier, France towards elucidation of the tri-dimensional organization of the pituitary gland. This work revealed the unexpected organization of pituitary cells into homotypic cell networks in which all cells of the same lineage contact similar cells, such that these cells exchange signals for the production of coordinated responses. In addition, these homotypic networks interact with each other as they are set up during organ development.

Mechanisms of cell specification
The investigation of transcriptional regulatory mechanisms for expression of pituitary hormone-coding genes led to discover a number of critical transcription factors such as the Pitx subfamily of homeodomain proteins, the Tbox factor Tpit, and more recently, the critical role of Pax7 as selector of intermediate pituitary identity. The research unit's members are using the full spectrum of genome technologies to identify other regulators of pituitary cell specification139 and in particular, they are investigating the mechanism used by Pax7 to pioneer chromatin remodelling and reshape the epigenome in order to program an alternate cell fate. Few factors have been shown to have pioneer activity and hence we have a unique system to understand how chromatin is reprogrammed.

Hormonal regulation of gene expression
Expression of the POMC gene is tightly regulated by central (brain) mediators or systemic (blood-borne) hormones such as glucocorticoids. The members have defined mechanisms of POMC gene activation by hypothalamic CRH as well as negative feedback regulation by glucocorticoids and their receptor GR. Both actions are mediated by transcription factors of the nuclear receptor family, either GR or orphan nuclear receptors of the Nur subfamily. Investigations have led to discovery of new response elements, of mechanisms involving protein-protein tethering that results in mutual antagonism (trans-repression) as well as to identification of key components of glucocorticoid-dependent repression of POMC. Furthermore, the members identified disregulation of these mechanisms in pituitary adenomas that cause Cushing disease. 

Cushing’s disease and pituitary adenomas
In addition to studies of glucocorticoid resistance in pituitary adenomas that cause Cushing disease, the research unit has also investigated the control of cell cycle in normal pituitary development and in these adenomas. This work led to identification of unique mechanisms for cell cycle exit in pituitary progenitors (stem cells) as opposed to the control of cell cycle and tissue maintenance in the adult gland.

Pioneer factors open a part of the epigenome and consequently change the fate of cells .
We use pioneer factor Pax7 and its role in specifying the identity of intermediate pituitary gland cells, in order to understand how a pioneer factor can access its targets in the inactive epigenome to open it and therefore allow the expression of a new repertory of genes. This opening of the chromatin in the epigenome happens in several stages and also implies a modification at the DNA level (genome) which imprints a long-term memory of the open chromatin state. This epigenetic memory is therefore imprinted with the identity of a cell as it was expressed by a repertory of genes which is unique to each cell.

A general mechanism to transform a cell into a hormone-producing factory.
We have identified two transcription factors (gene expression regulators) which are responsible for transforming pituitary cells into hormone-producing factories. These factors increase the protein synthesis capacity and all required structures to do so, as well as the formation of cellular organelles, such as secretory granules, which are necessary to hormone production. These regulatory factors, Creb3l2 and Xbp1, are put into place during development and their activity is also regulated by signalling pathways which respond to the energetic state of the organism. We study the relationship between this signalling and the control of the pituitary gland’s secretory capacity.