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Abstract
Transcriptional regulators are crucial in adipocyte differentiation. We now show that the homeodomain-containing transcription factor Prep1 is a repressor of adipogenic differentiation since its down-regulation (DR) in both ex vivo bone marrow-derived mesenchymal stromal cells (MSC) and in vitro 3T3-L1 preadipocytes significantly increases their adipogenic differentiation ability. Prep1 acts at a stage preceding the activation of the differentiation machinery because its DR makes cells more prone to adipogenic differentiation even in the absence of the adipogenic inducers. Prep1 DR expands the DNA binding landscape of C/EBPβ (CCAAT enhancer binding protein β) without affecting its expression or activation. The data indicate that Prep1 normally acts by restricting DNA binding of transcription factors to adipogenic enhancers, in particular C/EBPβ.
Highlights
Adipogenesis mostly takes place during embryonic development and childhood, it occurs in adult life, when 10% of fat cells annually renew[1]
Prep[1] does not control a specific “differentiating” mechanism, but rather predisposes the cells towards adipogenic differentiation; its possible role appears to be that of restricting DNA binding of transcription factors, in particular C/EBPβ, for example as a chromatin remodeling factor
We correlated the expression of Prep[1] and selected markers of adipogenic differentiation in wt and mutant mesenchymal stromal cells (MSC), before and after adipogenic induction (3 days)
Summary
Adipogenesis mostly takes place during embryonic development and childhood (in the mouse it starts immediately after birth and proceeds during the immediate postnatal days), it occurs in adult life, when 10% of fat cells annually renew[1]. Mature adipocytes derive from not yet well characterized mesenchymal stem (stromal) cells (MSC)[3], several proteins that regulate adipogenesis at different stages of differentiation have been identified mainly via in vitro experiments In this respect, activation of hormone signaling pathways and chromatin remodeling that occur within hours from induction are critically important[4,5,6]. In the preadipocyte cell line 3T3-L1, frequently used as a model to study the adipogenic process[8], the addition of insulin, dexamethasone and 3-isobutyl-1-methylxanthine (IBMX), referred to as the complete adipogenic differentiation cocktail, leads to the very early recruitment of transcription factors into well defined chromatin hotspots hosting multiple transcription factor binding sites characterized as adipogenic enhancers[9] These hotspots are always occupied by C/EBPβ, which appears to be the most-upstream triggering transcription factor, whereas Pparγ (Peroxisome proliferator-activated receptor gamma), one of the main players in the adipogenic lineage, seems to act downstream[10]. Prep[1] does not control a specific “differentiating” mechanism, but rather predisposes the cells towards adipogenic differentiation; its possible role appears to be that of restricting DNA binding of transcription factors, in particular C/EBPβ, for example as a chromatin remodeling factor
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