MECHANISMS IN ENDOCRINOLOGY: Pioneer transcription factors in pituitary development and tumorigenesis

Abstract

Pioneer transcription factors have key roles in development as master regulators of cell fate specification. Only a small fraction of all transcription factors have the pioneer ability that confers access to target genomic DNA sites embedded in so-called “closed” heterochromatin. This ability to seek and bind target sites within the silenced portion of the epigenome is the basis for their role in changing cell fate. Upon binding heterochromatin sites, pioneer factors trigger remodelling of chromatin from a repressed into an active organization. This action is typically exerted at enhancer regulatory sequences, thus allowing activation of new gene subsets. During pituitary development, the only pioneer with a well-documented role is Pax7 that specifies the intermediate lobe melanotrope cell fate. In this review, a particular focus is placed on this Pax7 function but its properties are also considered within the general context of pioneer factor action. Given their potent activity to reprogram gene expression, it is not surprising that many pioneers are associated with tumor development. Over-expression or chromosomal translocations leading to production of chimeric pioneers have been implicated in different cancers. We review here the current knowledge on the mechanism of pioneer factor action.

Integration of Epigenetic Mechanisms into Non-Genotoxic Carcinogenicity Hazard Assessment: Focus on DNA Methylation and Histone Modifications

“…For example, the half-life of histone acetylation marks is within a few minutes but those of methylation marks vary from less than a day to more than four days for H4K20me3 [110,111]. Therefore, given these differences in half-lives, the measurement of chemical effects on global genome changes in acetylation reflects induction of rapid disequilibrium in enzymatic reactions (necessary for the rapidly changing euchromatin), and as such, longer experiments may be required to investigate impacts on methylation marks and in slowly changing heterochromatin [112].…”

“…In relation to question 4, the importance of running the appropriate assays over a sufficiently long duration, as discussed herein, cannot be over emphasised for the detection of heritable changes. Genes from heterochromatin regions that become active during carcinogenesis under the influence of pioneering transcription factors require longer assessment delays before becoming detectable [112]. The investigation of DNA repeated sequences, the application of HTP-NGS epigenetic analyses demonstrating abnormal heritable epigenetic reprograming occurring in the absence of sustained exposure, and additional key events will help pinpoint the identification of NGTxC.…”

Steroidogenic Factor 1 Regulates Transcription of the Inhibin B Coreceptor in Pituitary Gonadotrope Cells

“…However, the closed chromatin state of the Tgfbr3l locus in gonadotropes of conditional knockout (cKO) mice suggests that SF-1 promotes chromatin accessibility through the recruitment of histone modifying enzymes (36)(37)(38).…”

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

“…The corticotrophs are the first cells to appear at e12.5 and reach terminal differentiation. Initially, these cells require the activation of the T-box transcription factor TPIT (TBX19), which is a pioneer factor also required for melanotroph differentiation [66,67]. For this reason, corticotrophs and melanotrophs (both expressing the Pomc gene) are classified as the TPIT-lineage.…”