Krüppel-like Factor-6 Promotes Preadipocyte Differentiation through Histone Deacetylase 3-dependent Repression of DLK1

Abstract

Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krü ppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis. Repression of Dlk1 requires HDAC3 deacetylase activity, which is recruited to the endogenous Dlk1 promoter where it interacts with KLF6. Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression.

Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

“…Moreover, increased serum AFP in HCC patients has been associated with histologically less differentiated state in some [39], but not all [40] studies. Similarly, in other tissues KLF6 contributes to corneal development [41], promotes adipogenesis [42], and is required for normal hematopoiesis and vasculogenesis during development [43].…”

HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics

“…Future studies aimed to map the HDAC3 region responsible for CK2 interaction would help clarifying these points. In a number of circumstances, HDAC3 is capable of establishing direct protein-protein interactions and displays biological activity independent of its recruitment in N-CoR/SMRT complexes, suggesting alternative mechanism(s) through which it can exert its transcriptional co-repression function in normal and tumor cells [94][95][96][97][98][99][100][101]. It would be tempting to speculate that HDAC3 phosphorylation might assume a critical role in activating the enzyme in N-CoR/SMRTindependent contexts.…”

A chromatin perspective of adipogenesis

“…In this sense, transcription factor KLF6 promotes adipogenesis by silencing the preadipocyte marker gene dlk1 through HDAC3 recruitment to the dlk1 promoter. 92 Accordingly, we have observed that the promoter region of dlk1 is acetylated in 3T3-L1 fibroblasts, when the gene is highly expressed, becoming progressively deacetylated throughout differentiation as the gene is gradually silenced. 50 On the initial phases of adipogenesis, PPARg is blocked by its association with a repressive pRb-HDAC3 complex resulting in the recruitment of deacetylase activity to PPARg target promoters and their consequent repression.…”