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Proprotein convertase subtilisin/kexin type 9 (PCSK9) impedes low-density lipoprotein (LDL) receptor (LDLR)-mediated LDL-cholesterol uptake and has hence emerged as a critical regulator of serum cholesterol levels and a new therapeutic target for the treatment of hypercholesterolemia. Statins have been shown to elevate circulating PCSK9 levels by stimulating PCSK9 gene transcription, which reduces the clinical efficacy of statin in LDL-cholesterol reduction. The transcription of PCSK9 is partially controlled by the hepatocyte nuclear factor 1 (HNF1) binding site embedded in the proximal region of its promoter. In this study, we utilized adenoviral shRNA delivery vectors to generate liver-specific knockdown of HNF1α (Ad-shHNF1α) or HNF1β (Ad-shHNF1β) in hamsters to examine the impact of reduced hepatic expression of HNF1 transcription factors on statin-induced elevation of PCSK9 expression and serum cholesterol levels. We showed that the administration of rosuvastatin (RSV) to normolipidemic hamsters significantly augmented hepatic PCSK9 expression and serum PCSK9 levels. In addition, RSV treatment increased hepatic HNF1α protein levels without a clear effect on HNF1α mRNA expression. Injection of Ad-shHNF1α or Ad-shHNF1β into hamsters both blunted RSV-induced elevation of PCSK9 serum concentration and hepatic mRNA and protein levels, which led to significant increases in liver LDLR protein abundance. Furthermore, hepatic depletion of HNF1 factors lowered circulating total cholesterol and non-high density lipoprotein cholesterol levels in RSV-treated hamsters. Our study demonstrates that both HNF1α and HNF1β are positive regulators of hepatic PCSK9 transcription in hamster species and that transient, liver-specific knockdown of either HNF1α or HNF1β could antagonize the RSV-induced elevation of serum PCSK9 and reduce circulating cholesterol levels.

Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the −309/−60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1β (HNF-1α/β) at −84/−68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1.

Objective: α-fetoprotein (AFP) expression is activated during the embryonic stage or hepatocellular carcinogenesis, so it is presumed that AFP is a key endogenous molecule to promote cell proliferation or differentiation. We carried out gene screening in an unknown family with hyper-alpha-fetoproteinemia and some sporadic menopausal women, and discussed the relationship between AFP expression and liver cirrhosis. Methods: Peripheral blood samples from family members, patients with malignant liver tumors, and normal controls were collected. Full-length sequence of AFP was amplified and directly sequenced, and compared with normal controls. HNF-1α and HNF-1β in plasma levels of family members, patients with liver cancer, newborns, pregnant women, and normal subjects were detected by ELISA, and the relationship between HNF-1 and AFP mutation or high expression was evaluated. Results: There was a mutation in AFP promoter region at c.-200 C>T, which was located at the binding site of AFP hepatocyte nuclear factor 1 (HNF-1). AFP was higher than 4000 ng/L in all members carrying the mutation, but liver cancer was excluded in the family with hyper-alpha-fetoprotein. However, cirrhosis occurred in post-menopausal women. The cases reviewed showed that unknown hyper-alpha-fetoprotein was closely related to HNF-1 binding point of AFP in post-menopausal women with cirrhosis (7/11), while the plasma levels of HNF-1α and HNF-1β were not significantly different. Conclusion: The mutation of the HNF-1 binding point of AFP may lead to an abnormal high expression of AFP by altering the binding of HNF transcription factors, which is closely related to cirrhosis in menopausal women.

The regulated expression of large human genes can depend on long-range interactions to establish appropriate three-dimensional structures across the locus. The cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encompasses 189 kb of genomic DNA, shows a complex pattern of expression with both spatial and temporal regulation. The flanking loci, ASZ1 and CTTNBP2, show very different tissue-specific expression. The mechanisms governing control of CFTR expression remain poorly understood, although they are known to involve intronic regulatory elements. Here, we show a complex looped structure of the CFTR locus in cells that express the gene, which is absent from cells in which the gene is inactive. By using chromatin conformation capture (3C) with a bait probe at the CFTR promoter, we demonstrate close interaction of this region with sequences in the middle of the gene about 100 kb from the promoter and with regions 3' to the locus that are about 200 kb away. We show that these interacting regions correspond to prominent DNase I hypersensitive sites within the locus. Moreover, these sequences act cooperatively in reporter gene constructs and recruit proteins that modify chromatin structure. The model for CFTR gene expression that is revealed by our data provides a paradigm for other large genes with multiple regulatory elements lying within both introns and intergenic regions. We anticipate that these observations will enable original approaches to designing regulated transgenes for tissue-specific gene therapy protocols.

Background Maturity-onset diabetes of the young type 5 (MODY5) is a rare subtype of MODYs. It is caused by mutations of the hepatocyte nuclear factor 1 homeobox b gene (HNF1B). 17q12 recurrent deletion syndrome usually results in MODY5 because of the deletion of HNF1B. These patients often have other clinical manifestations besides diabetes. Refractory hypomagnesemia was a clue for further examination in this patient. But she lacked structural abnormalities of the genitourinary system and neurodevelopmental disorders that are common manifestations in patients with 17q12 recurrent deletion syndrome. Some atypical patients deserved attention. Case presentation A 21-year-old young woman was admitted to our hospital for severe malnutrition and gastrointestinal symptoms. At age 20, she was diagnosed with type 2 diabetes mellitus (T2DM) and was administered oral antidiabetic drugs. Soon afterward, the patient discontinued the medication on her own accord and then went to the hospital again due to diabetic ketoacidosis. After insulin treatment, diabetic ketoacidosis was cured and blood glucose was controlled satisfactorily. But intractable nausea, vomiting, and persistent weight loss were stubborn. Further examination revealed that the patient had hypokalemia and hard rectification hypomagnesemia. Genetic testing revealed about 1.85 Mb heterozygous fragment deletion on chromosome 17 and deletion of exons 1–9 of HNF1B heterozygosity missing was approved. Finally, the patient was diagnosed MODY5. Discussion and Conclusions The 17q12 recurrent deletion syndrome is characterized by MODY5, structural or functional abnormalities of the kidney and urinary tract, and neurodevelopmental or neuropsychiatric disorders. This patient did not have any structural abnormalities of the genitourinary system and neuropsychiatric disorders, which is rare. She had experienced a period of misdiagnosis before being diagnosed with 17q12 recurrent deletion syndrome, and hypomagnesemia was an important clue for her diagnosis. Therefore, diabetic physicians should be alert to a special type of diabetes if patients have unexplained signs and symptoms. The absence of well-known features of HNF1B disease does not exclude MODY5.

Background Hepatitis B virus (HBV) infection is one of the most serious public health issues. Recent HBV genetic research has revealed novel genetic rearrangements termed complex structural variations (SVs), which are composed of combinations of SVs such as insertions, deletions, and duplications. An extensive search was made for complex SVs of HBV and their characteristics were analyzed. Results Fifty-five HBV strains with complex SVs were identified by analyzing genetic sequences of HBV with bioinformatical tools. Along with 15 HBV strains with complex SVs in a previous report, a total of 70 HBV strains harboring complex SVs were analyzed. Complex SVs in the HBV genome were located frequently between nt 1500 and 2000. Insertions were observed in 65/70 (92.9%) of HBV strains with complex SVs. As insertional motif sequences, hepatocyte nuclear factor 1 binding site, a sequence complementary to part of box α in enhancer II, and insertions of unknown origins were observed. The complex SVs were classified into six groups, and combination of insertion and deletion was observed more frequently than other patterns. Conclusion Through an extensive search of HBV sequences, new strains with complex SVs were identified in this study. Characteristics of HBV with complex SVs were clarified by the analysis of 70 HBV strains harboring complex SVs. Further investigation is required to elucidate its role in pathogenesis of HBV-related liver disease.

Here, we report phenotypic differences and similarities of monozygotic twins with maturity‐onset diabetes of the young type 5 harboring a partial deletion of chromosome 17q12. The proband and her twin sister manifested complete aplasia and marked hypoplasia, respectively, of the body and tail of the pancreas. Whereas both twins showed marked hypoplasia of the right kidney and multiple cysts in both kidneys, only the proband's sister showed hydronephrosis in the left kidney. The proband had profound defects in insulin and glucagon secretion, as well as mild renal dysfunction, whereas her sister had pronounced renal dysfunction accompanied by mild defects in insulin and glucagon secretion. Both twins manifested hypomagnesemia and hyperuricemia, but no apparent liver dysfunction or intellectual disability. The severity of renal and pancreatic defects differed between monozygotic twins with maturity‐onset diabetes of the young type 5, suggesting that the phenotypes of this condition are determined not solely by genetic factors. Abdominal CT (a–c) and T2‐weighted MRI (d, e) for Twin 1 (a, d) and Twin 2 (b, c, e). The boundary of the pancreas is outlined in red (a–c). CT shows a small pancreatic head and complete deficiency of the pancreatic body and tail in Twin 1 (a) as well as hypoplasia of the pancreatic body and tail in Twin 2 (b, c).

CD8 + T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality—which is referred to as T cell exhaustion 1 , 2 —is maintained by precursors of exhausted T (T PEX ) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1 − exhausted effector T cells 3 – 6 . Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L + T PEX cells. The transcription factor MYB is not only essential for the development of CD62L + T PEX cells and maintenance of the antiviral CD8 + T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L + T PEX cells and depends on MYB. Our findings identify CD62L + T PEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity. CD62L +  precursors of exhausted T cells retain long-term proliferative potential, multipotency and repopulation capacity, and the transcription factor MYB is essential for the development and function of this population of cells.

TCF1 and its homologue LEF1 are historically known as effector transcription factors downstream of the WNT signalling pathway and are essential for early T cell development. Recent advances bring TCF1 into the spotlight for its versatile, context-dependent functions in regulating mature T cell responses. In the cytotoxic T cell lineages, TCF1 is required for the self-renewal of stem-like CD8+ T cells generated in response to viral or tumour antigens, and for preserving heightened responses to checkpoint blockade immunotherapy. In the helper T cell lineages, TCF1 is indispensable for the differentiation of T follicular helper and T follicular regulatory cells, and crucially regulates immunosuppressive functions of regulatory T cells. Mechanistic investigations have also identified TCF1 as the first transcription factor that directly modifies histone acetylation, with the capacity to bridge transcriptional and epigenetic regulation. TCF1 also has the potential to become an important clinical biomarker for assessing the prognosis of tumour immunotherapy and the success of viral control in treating HIV and hepatitis C virus infection. Here, we summarize the key findings on TCF1 across the fields of T cell immunity and reflect on the possibility of exploring TCF1 and its downstream transcriptional programmes as therapeutic targets for improving antiviral and antitumour immunity.The transcription factor TCF1 is essential for early T cell development, and recent advances have uncovered context-dependent functions in mature T cells. This review summarizes key findings on TCF1 across the field of T cell immunity and explores their translational potential.

Aims/hypothesisTreatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years.MethodsThis was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate.ResultsA total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years’ follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m2) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis.Conclusions/interpretationIn participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA1c.