HMGB2 orchestrates mitotic clonal expansion by binding to the promoter of C/EBPβ to facilitate adipogenesis

Abstract

High-mobility group box 2 (HMGB2) is an abundant, chromatin-associated protein that plays an essential role in the regulation of transcription, cell proliferation, differentiation, and tumorigenesis. However, the underlying mechanism of HMGB2 in adipogenesis remains poorly known. Here, we provide evidence that HMGB2 deficiency in preadipocytes impedes adipogenesis, while overexpression of HMGB2 increases the potential for adipogenic differentiation. Besides, depletion of HMGB2 in vivo caused the decrease in body weight, white adipose tissue (WAT) mass, and adipocyte size. Consistently, the stromal vascular fraction (SVF) of adipose tissue derived from hmgb2−/− mice presented impaired adipogenesis. When hmgb2−/− mice were fed with high-fat diet (HFD), the body size, and WAT mass were increased, but at a lower rate. Mechanistically, HMGB2 mediates adipogenesis via enhancing expression of C/EBPβ by binding to its promoter at “GGGTCTCAC” specifically during mitotic clonal expansion (MCE) stage, and exogenous expression of C/EBPβ can rescue adipogenic abilities of preadipocytes in response to HMGB2 inhibition. In general, our findings provide a novel mechanism of HMGB2-C/EBPβ axis in adipogenesis and a potential therapeutic target for obesity.

SESN3 Inhibited SMAD3 to Relieve Its Suppression for MiR-124, Thus Regulating Pre-Adipocyte Adipogenesis

“…Hence, we consider that SESN3 regulated pre-adipocyte adipogenesis through inhibiting its proliferation effect, and then further suppressing differentiation. There are some reports that also concur this idea: For instance, the inhibition effect of HMGB2 and KDM5 for pre-adipocytes thus suppressed adipogenesis [ 39 , 40 , 41 ].…”

Regulatory mechanisms of the early phase of white adipocyte differentiation: an overview

“…Several factors and proteins regulate this process by interacting with C/EBPβ [ 46 ]. Very recently, a protein belonging to the non-histone chromosomal high mobility group protein family, the High Mobility Group Box 2 (HMGB2), has been studied in the early phase of adipogenesis.…”

“…The peak of expression of this protein is at 24 h after differentiation induction, while its expression decreases during the late stage. It was then observed that the HMGB2 knockdown, 72 h before adding adipogenic stimuli, impairs adipogenesis while the downregulation 48 h after the induction of adipogenesis does not affect terminal differentiation [ 46 ]. Thus, the mechanism by which this protein plays a role during the mitotic clonal expansion is through the binding to the C/EBPβ promoter, stimulating the transcription of factors essential for proper adipocytes differentiation.…”

“…Thus, the mechanism by which this protein plays a role during the mitotic clonal expansion is through the binding to the C/EBPβ promoter, stimulating the transcription of factors essential for proper adipocytes differentiation. Conversely, when HMGB2 is removed, the expression of C/EBPβ is lower, and mitotic clonal expansion does not occur properly, causing the formation of smaller adipocytes thus reducing body size in vivo [ 46 ].…”

“…It slows the cell cycle by increasing transcription of p21 and FKBPL, hence favoring p21 mRNA stability. PPARγ ultimately induces a competitive mechanism between cyclin D1 and p21 expression controlling the number of cells that remain in proliferation or proceed to terminal differentiation [ 45 ] HMGB2 Highly expressed in the first 24 h of adipogenesis, it favors the expression of C/EBPβ, cell cycle exit, and adipocyte differentiation [ 46 ] Spry1 Its expression level increases in the early phases of adipogenesis and acts as a negative regulator of MAPK signaling to favor cell cycle exit and boost the adipogenic program [ 47 ] MED20 It directly interacts with the RNA polymerase II and C/EBPβ to favor the transcription of PPARγ [ 49 ] PARP-1 Involved in the PARylation of C/EBPβ, inhibiting its ability to bind to DNA and hence blocking the adipogenic program. Nuclear PARP-1 is required during terminal differentiation to block the transcriptional activity of C/EBPβ [ 50 ] …”