Histone Demethylase LSD1 Regulates Adipogenesis

Abstract

Epigenetic mechanisms, in particular the enzymatic modification of histones, are a crucial element of cell differentiation, a regulated process that allows a precursor cell basically to turn into a different cell type while maintaining the same genetic equipment. We have previously described that the promoters of adipogenic genes display significant levels of dimethylation at the Lys 4 of histone H3 (H3K4) in preadipocytes, where these genes are still silenced, thus maintaining the chromatin of the precursor cell in a receptive state. Here, we show that the expression of several histone demethylases and methyltransferases increases during adipogenesis, suggesting an important role for these proteins in this process. Knockdown of the H3K4/K9 demethylase LSD1 results in markedly decreased differentiation of 3T3-L1 preadipocytes. This outcome is associated with decreased H3K4 dimethylation and increased H3K9 dimethylation at the promoter of transcription factor cebpa, whose expression must be induced >200-fold upon stimulation of differentiation. Thus, our data suggest that LSD1 acts to maintain a permissive state of the chromatin in this promoter by opposing the action of a H3K9 methyltransferase. Knockdown of H3K9 methyltransferase SETDB1 produced the opposite results, by decreasing H3K9 dimethylation and increasing H3K4 dimethylation levels at the cebpa promoter and favoring differentiation. These findings indicate that the histone methylation status of adipogenic genes as well as the expression and function of the proteins involved in its maintenance play a crucial role in adipogenesis.

Suv39h1 Mediates AP-2α-Dependent Inhibition of C/EBPα Expression during Adipogenesis

“…Previous studies have shown that H3K9me2 is enriched on the promoters of C/EBP␣ and PPAR␥ in preadipocytes and decreases with the increase of H3K4me3 during differentiation (29,46). But it is poorly understood whether H3K9me3 contributes to the repression of C/EBP␣ in the early stages of differentiation and whether Suv39h1 has any function during adipogenesis.…”

Adipogenesis at a glance

“…For example, Pax-transactivationdomain-interacting protein  (PTIP, officially known as PAXIP1) regulates the expression of both C/EBP and PPARg by controlling recruitment of the histone 3 lysine 4 (H3K4) methyltransferase MLL4, as well as DNA polymerase II, to their promoters (Cho et al, 2009). In addition, the lysine-specific histone demethylase 1A (KDM1A, also known as LSD1) and the H3K9 methyltransferase SET domain, bifurcated 1 (SETDB1) exhibit opposing effects by promoting and inhibiting adipogenesis, respectively (Musri et al, 2010). It has been proposed that SETDB1 maintains the promoter for the gene encoding C/EBP in a silent state, but that recruitment of LSD1 increases upon differentiation, permitting induction of C/EBP expression (Musri et al, 2010).…”

“…In addition, the lysine-specific histone demethylase 1A (KDM1A, also known as LSD1) and the H3K9 methyltransferase SET domain, bifurcated 1 (SETDB1) exhibit opposing effects by promoting and inhibiting adipogenesis, respectively (Musri et al, 2010). It has been proposed that SETDB1 maintains the promoter for the gene encoding C/EBP in a silent state, but that recruitment of LSD1 increases upon differentiation, permitting induction of C/EBP expression (Musri et al, 2010).…”

Contribution of epigenetics in diabetic retinopathy

“…There are two major types of HMTs, lysine-specific, which can be SET (Su(var)3-9, Enhancer of Zeste, Trithorax) domain containing or non-SET domain containing. Contrary to a relatively well defined histone methylating system, histone demethylation machinery is not well studied; LSD1, a lysine-specific histone demethylase, specifically removes methyl group from H3K4me and H3K9me [36,37].…”