Abstract
Transcription factor 19 (TCF19) has been reported as a type 1 diabetes-associated locus involved in maintenance of pancreatic β cells through a fine-tuned regulation of cell proliferation and apoptosis. TCF19 also exhibits genomic association with type 2 diabetes, although the precise molecular mechanism remains unknown. It harbors both a plant homeodomain and a forkhead-associated domain implicated in epigenetic recognition and gene regulation, a phenomenon that has remained unexplored. Here, we show that TCF19 selectively interacts with histone 3 lysine 4 trimethylation through its plant homeodomain finger. Knocking down TCF19 under high-glucose conditions affected many metabolic processes, including gluconeogenesis. We found that TCF19 overexpression represses de novo glucose production in HepG2 cells. The transcriptional repression of key genes, induced by TCF19, coincided with NuRD (nucleosome-remodeling-deacetylase) complex recruitment to the promoters of these genes. TCF19 interacted with CHD4 (chromodomain helicase DNA-binding protein 4), which is a part of the NuRD complex, in a glucose concentration-independent manner. In summary, our results show that TCF19 interacts with an active transcription mark and recruits a co-repressor complex to regulate gluconeogenic gene expression in HepG2 cells. Our study offers critical insights into the molecular mechanisms of transcriptional regulation of gluconeogenesis and into the roles of chromatin readers in metabolic homeostasis.
Highlights
Transcription factor 19 (TCF19) has been reported as a type 1 diabetes–associated locus involved in maintenance of pancreatic  cells through a fine-tuned regulation of cell proliferation and apoptosis
Because our observations indicate that TCF19 responds to hormonal activators and repressors of gluconeogenesis, we further proceeded to investigate the occupancy of TCF19 at gluconeogenic gene promoters under the influence of either cAMP/dexamethasone or insulin
Blood glucose homeostasis is established by a fine balance of transcriptional regulation by specific hormones and circulating nutrients
Summary
G6P/G6PC, glucose-6-phosphatase; TCF19, transcription factor 19; PHD, plant homeodomain; FBP1, fructose-1,6-bisphosphatase; PCK1, pyruvate carboxyl kinase 1; NuRD, nucleosome remodeling deacetylase; CHD4, chromodomain helicase DNA-binding protein 4; CREB, cAMP-response element-binding protein; CRTC2, CREBregulated transcription co-activator 2; PGC-1␣, peroxisome proliferatoractivated receptor ␥ co-activator 1␣; HDAC, histone deacetylase; NAV1.2, sodium channel, voltage-gated, type II; IRE, insulin response element; T2D, type 2 diabetes; LG, low glucose; HG, high glucose; GO, gene ontology; DEG, differentially expressed gene; IP, immunoprecipitation; H3 and H4, histone H3 and H4, respectively; Me2 and Me3, diand trimethylation, respectively; Ac, acetylation. TCF19 regulates gluconeogenesis tion status of PGC-1␣ was found to be different in diabetic patients [8]. We focus on a previously unexplored role of transcription factor 19 (TCF19) as an important regulator of the key gluconeogenic genes. Microarray analysis on TCF19-depleted cells showed a global effect on metabolic pathways, and interestingly, the gluconeogenic genes were significantly up-regulated. Physical interaction of TCF19 with CHD4 and MTA1 and their co-recruitment onto promoters of gluconeogenic genes in high-glucose conditions suggest that the observed repression is possibly mediated in concert with NuRD complex, of which CHD4 and MTA1 are an integral part [19, 20]. More in-depth analysis revealed how TCF19 exerts a repressive effect on the gluconeogenic genes by integrating the hormonal and metabolic cues via its PHD finger interactions with chromatin. TCF19 could be an important target in modulating the glucose homeostasis in cells
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