Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress

Bochkis, Irina M.; Rubins, Nir; White, Peter; Furth, Emma E.; Friedman, Joshua R.; Kaestner, Klaus H.

doi:10.1038/nm.1853

Cited by 174 publications

(201 citation statements)

References 56 publications

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“…MeCP2, usually overexpressed in human carcinomas, promotes the growth and invasiveness of many types of cancer cells, including breast carcinoma cells (Billard et al, 2002;Ray et al, 2013), and may modulate ABCB1/MDR1 expression (El-Osta and Wolffe, 2001). FOXA2, a transcription factor belonging to the forkhead class of DNA-binding proteins, is revealed as an important regulator in promoting pancreatic/hepatic/colorectal cell differentiation and organ development (Gao et al, 2008;Song et al, 2010) and regulating the expression of some (proto-)oncogenes ) and a number of ABC transporters (Bochkis et al, 2008(Bochkis et al, , 2012. Therefore, reduction of MeCP2 and FOXA2 protein levels may at least partially provide an explanation for miR-1291 in suppressing cancer cell proliferation Bi et al, 2014) and enhancing chemosensitivity.…”

Section: Discussionmentioning

confidence: 99%

Chimeric MicroRNA-1291 Biosynthesized Efficiently in Escherichia coli Is Effective to Reduce Target Gene Expression in Human Carcinoma Cells and Improve Chemosensitivity

Addepalli

et al. 2015

Drug Metab Dispos

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In contrast to the growing interests in studying noncoding RNAs (ncRNAs) such as microRNA (miRNA or miR) pharmacoepigenetics, there is a lack of efficient means to cost effectively produce large quantities of natural miRNA agents. Our recent efforts led to a successful production of chimeric pre-miR-27b in bacteria using a transfer RNA (tRNA)-based recombinant RNA technology, but at very low expression levels. Herein, we present a high-yield expression of chimeric pre-miR-1291 in common Escherichia coli strains using the same tRNA scaffold. The tRNA fusion pre-miR-1291 (tRNA/mir-1291) was then purified to high homogeneity using affinity chromatography, whose primary sequence and posttranscriptional modifications were directly characterized by mass spectrometric analyses.

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Section: Discussionmentioning

confidence: 99%

Chimeric MicroRNA-1291 Biosynthesized Efficiently in Escherichia coli Is Effective to Reduce Target Gene Expression in Human Carcinoma Cells and Improve Chemosensitivity

Addepalli

et al. 2015

Drug Metab Dispos

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“…Protein extracts preparation and protein immunoblot analysis were performed as reported previously (Bochkis et al., 2008). The primary antibodies used were rabbit antibody to FOXA2 (Seven Hills Bioreagents, WRAB‐1,200, 1:5,000), rabbit antibody to histone H3 (Cell Signaling #4,499), goat antibody to LAMIN A/C (Santa Cruz, sc‐7,196, 1:100), goat antibody to LAMIN B (Santa Cruz, sc‐6,215, 1:100), rabbit antibody to LAMIN B (Abcam, ab16048), and rabbit antibody to TBP (Santa Cruz, sc‐273, 1:100).…”

Section: Methodsmentioning

confidence: 99%

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

et al. 2018

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SummaryIncreasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age‐dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina‐associated domains (LADs) using lamin B1 ChIP‐Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1‐associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24‐deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de‐repression of PPAR‐ and LXR‐dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de‐repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

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“…The intrahepatic bile acid levels were also determined using a Bile Acid L3K Assay Kit (Diagnostic Chemicals) according to the manufacturer's directions (Bochkis et al, 2008).…”

Section: Liver Chemistry Testsmentioning

confidence: 99%

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

et al. 2013

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SUMMARYCongenital biliary atresia is an incurable disease of newborn infants, of unknown genetic causes, that results in congenital deformation of the gallbladder and biliary duct system. Here, we show that during mouse organogenesis, insufficient SOX17 expression in the gallbladder and bile duct epithelia results in congenital biliary atresia and subsequent acute 'embryonic hepatitis', leading to perinatal death in ~95% of the Sox17 heterozygote neonates in C57BL/6 (B6) background mice. During gallbladder and bile duct development, Sox17 was expressed at the distal edge of the gallbladder primordium. In the Sox17 +/-B6 embryos, gallbladder epithelia were hypoplastic, and some were detached from the luminal wall, leading to bile duct stenosis or atresia. The shredding of the gallbladder epithelia is probably caused by cell-autonomous defects in proliferation and maintenance of the Sox17 +/-gallbladder/bile duct epithelia. Our results suggest that Sox17 plays a dosage-dependent function in the morphogenesis and maturation of gallbladder and bile duct epithelia during the late-organogenic stages, highlighting a novel entry point to the understanding of the etiology and pathogenesis of human congenital biliary atresia.

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Hepatocyte-specific ablation of Foxa2 alters bile acid homeostasis and results in endoplasmic reticulum stress

Cited by 174 publications

References 56 publications

Chimeric MicroRNA-1291 Biosynthesized Efficiently in Escherichia coli Is Effective to Reduce Target Gene Expression in Human Carcinoma Cells and Improve Chemosensitivity

Chimeric MicroRNA-1291 Biosynthesized Efficiently in Escherichia coli Is Effective to Reduce Target Gene Expression in Human Carcinoma Cells and Improve Chemosensitivity

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver

Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

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