The selector gene Pax7 dictates alternate pituitary cell fates through its pioneer action on chromatin remodeling

Abstract

The anterior and intermediate lobes of the pituitary gland derive from the surface ectoderm. They provide a simple system to assess mechanisms of developmental identity established by tissue determinants. Each lobe contains a lineage expressing the hormone precursor pro-opiomelanocortin (POMC): the corticotropes and melanotropes. The T-box transcription factor Tpit controls terminal differentiation of both lineages. We now report on the unique role of Pax7 as a selector of intermediate lobe and melanotrope identity. Inactivation of the Pax7 gene results in loss of melanotrope gene expression and derepression of corticotrope genes. Pax7 acts by remodeling chromatin and allowing Tpit binding to a new subset of enhancers for activation of melanotrope-specific genes. Thus, the selector function of Pax7 is exerted through pioneer transcription factor activity. Genome-wide, the Pax7 pioneer activity is preferentially associated with composite binding sites that include paired and homeodomain motifs. Pax7 expression is conserved in human and dog melanotropes and defines two subtypes of pituitary adenomas causing Cushing's disease. In summary, expression of Pax7 provides a unique tissue identity to the pituitary intermediate lobe that alters Tpit-driven differentiation through pioneer and classical transcription factor activities.

Treatment of Cushing's disease: a mechanistic update

“…POMC, PC2, and D2R (DRD2)) and these cells switched towards the corticotrope lineage. Similar observations were made using AtT20 mice corticotrope adenoma cells (Budry et al 2012). The hypothesis that adenomatous hyperplasia or corticotrope hyperplasia is particularly sensitive to dopamine D2 receptor agonists (Lamberts et al 1982), and SSTR5 expression appears to be lower than that in the pure adenomas awaits further confirmation (Budry et al 2012).…”

“…Finally, increased NF expression indicates close proximity of these lesions to the posterior pituitary lobe. PAX7, a protein restricted to the melanotrope lineage of the intermediate pituitary lobe that is not expressed in the anterior corticotrope cells, was identified as a key regulator that drives POMC-positive pituitary cells toward melanotrope differentiation (Budry et al 2012). In the intermediate lobe, cells of rat pituitary glands lacking PAX7 showed downregulation of melanotrope-specific genes (e.g.…”

Pioneer transcription factors in cell reprogramming

“…In pituitary melanotrope development, the initial expression of Pax7, a paired homeodomain transcription factor, slightly precedes the other melanotrope transcription factors, such as Tpit (Budry et al 2012). Budry et al (2012) exogenously expressed Pax7 in a pituitary corticotrope cell line in which Tpit is expressed but Pax7 is not. Exogenous Pax7 binding increased chromatin accessibility and induced de novo Tpit recruitment at the Pax7-binding sites.…”

Many roles for Pax7

“…4 and some others in pituitary melanotropes of the intermediate lobe. 5 The expression of Pax7 in fibroblasts is surprising, although the authors note that some studies suggested such a possibility. 6 However, Pax7 expressing cells in wound repair 6 may in fact be SCs from the dermal panniculus carnosus muscle present in the rodents' skin.…”