Choline Kinase Alpha Is a Novel Transcriptional Target of the Brg1 in Hepatocyte: Implication in Liver Regeneration

Abstract

Liver regeneration is a key compensatory process in response to liver injury serving to contain damages and to rescue liver functions. Hepatocytes, having temporarily exited the cell cycle after embryogenesis, resume proliferation to regenerate the injured liver parenchyma. In the present study we investigated the transcriptional regulation of choline kinase alpha (Chka) in hepatocytes in the context of liver regeneration. We report that Chka expression was significantly up-regulated in the regenerating livers in the partial hepatectomy (PHx) model and the acetaminophen (APAP) injection model. In addition, treatment with hepatocyte growth factor (HGF), a strong pro-proliferative cue, stimulated Chka expression in primary hepatocytes. Chka depletion attenuated HGF-induced proliferation of hepatocytes as evidenced by quantitative PCR and Western blotting measurements of pro-proliferative genes as well as EdU incorporation into replicating DNA. Of interest, deletion of Brahma-related gene 1 (Brg1), a chromatin remodeling protein, attenuated Chka induction in the regenerating livers in mice and in cultured hepatocytes. Further analysis revealed that Brg1 interacted with hypoxia-inducible factor 1 alpha (HIF-1α) to directly bind to the Chka promoter and activate Chka transcription. Finally, examination of human acute liver failure (ALF) specimens identified a positive correlation between Chka expression and Brg1 expression. In conclusion, our data suggest that Brg1-dependent trans-activation of Chka expression may contribute to liver regeneration.

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“…RNA was extracted by using the RNeasy RNA isolation kit (Qiagen). Reverse transcriptase reactions were performed using a SuperScript First-strand Synthesis System (Invitrogen) as previously described [ 65 , 66 ]. Real-time PCR reactions were performed on an ABI Prism 7500 system with the following primers: ICAM-1 , 5'-AGCGGCTGACGTGTGCAGTAAT-3' and 5'-TCTGAGACCTCTGGCTTCGTCA-3'; SIRT6, 5'-TGGCAGTCTTCCAGTGTGGTGT-3' and 5'-CGCTCTCAAAGGTGGTGTCGAA-3'; DNMT1 , 5'-AGGTGGAGAGTTATGACGAGGC-3' and 5'-GGTAGAATGCCTGATGGTCTGC-3'.…”

Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis

“…Transient transfection was performed with Lipofectamine 2000. Cells were harvested 48 h after transfection and reporter activity was measured using a luciferase reporter assay system (Promega) as previously described ( Kong et al, 2021a , c ; Liu et al, 2021c ; Zhang et al, 2021 ). MS-275 and MC-1568 were purchased from Selleck.…”

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“…Whole cell lysates were obtained by re-suspending cell pellets in RIPA buffer (50 mM Tris pH7.4, 150 mM NaCl, 1% Triton X-100) with freshly added protease inhibitor (Roche) as previously described ( Hong et al, 2020 ; Dong et al, 2021 ; Kong et al, 2021a ; Li et al, 2021 ). Nuclear proteins were extracted using the NE-PER Kit (Pierce) following manufacturer’s recommendation.…”