Adipogenesis is governed by a robust gene regulatory network. Understanding how this network functions provides insights into pathological conditions, such as obesity and lipodystrophy, and represents an important step toward the rational design of targeted therapeutic interventions for these metabolic disorders.
This study has shown that the zinc finger factor ZNF638 is a novel regulator of the early phases of adipocyte differentiation. Several lines of evidence support this claim. First, ZNF638 is regulated specifically during the early phases of adipogenic differentiation, with its levels declining as adipocytes fully mature. Second, regulation of ZNF638 parallels the induction of C/EBPβ and C/EBPδ, known early regulators of adipogenesis, and the gain or loss of ZNF638 affects PPARγ expression and adipocyte differentiation. Finally, ZNF638 interacts with C/EBPs to control the expression of PPARγ.
ZNF638 was previously reported to be expressed in a variety of human cancer cell lines (9
) and tumors (11
) and in the mouse heart (9
). Our finding that ZNF638 expression has a temporal specific pattern during early adipogenesis suggests a novel role for this factor in mesenchymal differentiation. Previously, based on its sequence and domain composition, the cellular function of ZNF638 was inferred to have a putative role in splicing and DNA/RNA binding (10
). However to date, no in vivo
data have shown whether ZNF638 is involved in any of these predicted functions. Although the human homolog of ZNF638, NP220, was previously reported to directly interact with the transcription cofactor FHL2 and shuttle it to the nuclear compartment (12
), ZNF638 has not been implicated in a direct interaction with a transcription factor. Our results demonstrate that C/EBPs recruit ZNF638 to the PPARγ promoter, supporting a role for this zinc finger factor as a transcription cofactor.
During adipocyte differentiation, ZNF638 is driven by its RS domain to localize in nuclear speckles. Because speckles represent areas for storage of splicing factors, the presence of ZNF638 in a speckled pattern suggests that it may co-localize with proteins involved in splicing and play a potential role in coupling transcription to RNA processing, a similar role to what was previously demonstrated for PGC-1α (13
). Interestingly, in addition to their role in transcription, several known coactivators are also involved in pre-mRNA splicing (14
). It remains to be determined whether ZNF638 is also a dual function cofactor.
Our study highlights the role of ZNF638 in regulating early fat differentiation and characterizes it as a novel cofactor. An analogous role in adipogenesis has been previously attributed to the transcription coactivator SRC-3, which is also activated early in differentiation and induces PPARγ expression by cooperating with C/EBPs (6
). Despite the similarity of ZNF638 to SRC-3 with regard to its ability to physically and functionally interact with C/EBPs on the PPARγ promoter, ZNF638 differs from SRC-3 in that it lacks domains involved in histone modification. Additionally, the presence of multiple conserved motifs in this zinc finger factor may suggest that ZNF638 could function as an adaptor molecule to assemble other proteins in a functional transcription complex. Future experiments will determine whether ZNF638 functions by recruiting chromatin-remodeling factors or components of the transcriptional machinery to potentiate transcription. Finally, it will be of interest to determine whether hormonal cues modify the activity of ZNF638 to promote its functions during the early phases of adipocyte differentiation.