Page 12 - GPD-3-3

Gene & Protein in Disease Comprehensive analysis of ZNF521/Zfp521

controls adipose progenitor differentiation by transliterating ZNF521/Zfp521 is involved in the homeostasis regulation
PPARγ. 5,66,67 In early adipocyte differentiation, ZNF521 is a of hematopoietic, neural, and osteoadipogenic cells.
8,14
key regulator of early adipogenesis commitment. 51,68 EBF1 Forced over expression of ZNF521 in cells will lead to a
is a pro-lipogenic transcription factor that activates ZFP423 significant delay and decrease in adipocyte differentiation
expression and activity. 47,50,66,69 Zfp521 acts upstream to despite the action of adipogenic factors. 33,51 In contrast,
repress Zfp423 and EBF1 by physical interactions. 5,7,47 silencing ZNF521 significantly enhances the adipogenic
70
ZNF521 binds to its core domain to counter the trans- differentiation ability of hADSCs. 30,33 ZNF521 partially
activation of several target genes involved in B lymphopoiesis inhibits adipogenesis by inhibiting EBF1. 33,50,51 Siah2 is
and lipogenesis. However, as differentiation progresses, predominantly expressed in PDGFRα+ preadipocytes.
EBF1 suppresses Zfp521 expression by directly binding Siah2, ZNF521, and EBF1 can form a complex to regulate
to the inclusion enhancers. Zfp521 and EBF1 participate the degradation of ZNF521. 50,54 Taken together, these results
47
in negative feedback loops during fat commitment and confirm the role of ZNF521 as a key negative regulator of
differentiation. 5,47,50,51 adipose differentiation. There is a complex co-regulatory
33
BMP signaling promotes mesenchyme progenitor interaction between ZNF521, Siah2 and EBF1, thereby
cell differentiation. Zfp521 intrinsically blocks Zfp423 regulating the protein level of ZNF521. 50
expression by maintaining both Zfp423 promoters and 4.2. ZNF521/Zfp521 functions in osteogenic
enhancers in a transcriptionally silent state. In the absence differentiation
of Zfp521, Zfp423 expression is triggered, allowing either
BMP or pro-adipogenic stimulators to further stimulate Bone homeostasis is maintained by the coupling of
Zfp423 expression, resulting in excessive adipogenic hematopoietic osteoclasts (OCs) and mesenchyme
7,42
lineage commitment. 51 osteoblasts (OBs). Among them, the role of OBs
is to boost bone formation by stimulating some
3.4. ZNF521/Zfp521 involved in cellular signaling neurotransmitter mechanisms, calcium deposition, and
Zfp521 enhances B-cell receptor signaling and interferes bone regrowth/reconstruction, while the hematopoietic
with the IL-7/IL-7 receptor-mediated maturation pathway. absorption function of OCs is to absorb and dissolve old
38
Zfp521 mediates the NF-κB pathway through RELA bone by continuously secreting acidic substances from
7,71
and regulates the ability of HSC to exert both silencing aged bone. Across OBs and OCs, Zfp521 affects bone
and self-renewal effects. Zfp521 regulates quiescence in remodeling (bone resorption: osteoclasts digest old bone;
sternzellen by controlling the RELA-mediated NF-κB reversion: bone surface mononuclear cells; formation:
signaling pathway. Zfp521 transcriptionally represses the osteoblasts form new bone until the absorbed bone is
expression of Rela. Down regulation of Rela inhibits the completely replaced), thus positively affecting bone
hyperactivated NF-κB pathway and reverses the gradual homeostasis. 71
loss of Zfp521-null sternzellen under stress. 37 The exploration of osteoblast biosynthesis and

3.5. Zfp521, Zfp423 and EBF1 regulatory loop metabolic pathways showed that Zfp521 is highly expressed
in the edge of mesenchyme condensation and developing
EBF1 is an adipogenic transcription factor, and Zfp521 bones, 15,44,55 including chondrocytes, hypertrophic
antagonizes the adipogenic activity of ZFP423 by binding to chondrocytes, periosteum, osteoblasts, preosteoblasts,
EBF1. 47,51 As fat formation progresses, EBF1 inhibits Zfp521 and osteocytes. 9,13,55 In addition, Zfp521 is also highly
transcription in a negative feedback loop 47,50 (Figure 2). These expressed in C3H10T1/2 mesenchyme cell lines and
44
results suggest that the regulation of Zfp521 and EBF1 protein primary skull Obs. Forced expression of Zfp521 in
42
levels helps preadipocytes participate in fat formation. 33,47,50,68 osteoblasts can increase bone formation and mass. In
2
However, over expression of Zfp521 in preadipocytes contrast, over expression of Zfp521 in vitro antagonizes or
significantly inhibits their adipogenic potential. 47,63 inhibits osteoblast differentiation and nodule formation.
2,41
4. Roles of ZNF521/Zfp521 in cell The regulation of Zfp521 on osteoblasts is not only related
to cell type but also related to the cell development period.
differentiation In particular, it represses early osteoblast differentiation
4.1. ZNF521/Zfp521 acts on adipogenic but facilitates late osteoblast maturation. 24,30,59
differentiation In the growth plate, the expression intensity of Zfp521 is
MSCs are pluripotent progenitor cells that exist in bone different in each layer of chondrocytes, but the expression
19
marrow stromal cells and abdominal subcutaneous level is the highest in the cells before thickening. In
adipose tissue. Stem cell-associated transcription cofactor addition, Zfp521 is expressed at all stages of osteoblast
33
Volume 3 Issue 3 (2024) 6 doi: 10.36922/gpd.3260