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1.
J Infect Chemother ; 25(10): 769-773, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31023569

RESUMO

BACKGROUND: Serum Helicobacter pylori (H. pylori) antibody kits (LZ and LIA) using the latex agglutination immunoassay method are commercially available, but few studies have been performed to determine their diagnostic accuracy or to compare their results with those of enzyme-linked immunosorbent assay (ELISA) kits (EP and EIA). METHODS: Sera were obtained from 213 hospital outpatients with dyspeptic symptoms. The serological results were compared with the result of the 13C-urea breath test (UBT) which seems to be reliable. RESULTS: Of the 213 subjects, 154 were diagnosed as positive for H. pylori infection according to the UBT. The sensitivities and specificities of these tests were 97.4% and 76.3%, 98.1% and 78.0%, 99.4% and 74.6%, and 98.1% and 71.2% for the EP, LZ, EIA and LIA tests, respectively. When the 13 subjects whose seropositive results of the four kits were completely opposite to the negative results of the UBT were excluded, the specificities of evaluated kits were all higher than 90%. The concordance rate between the EP and EIA tests was 98.1% (Spearman's rank correlation coefficient = 0.83) and that between the LZ and LIA tests was 97.1% (correlation coefficient = 0.91). The LZ gave higher antibody titer value than EP (p < 0.0001, Z = 9.82; Wilcoxon signed-rank test), and EIA gave higher value than LIA (p < 0.0001, Z = 6.43; Wilcoxon signed-rank test). CONCLUSIONS: The latex immunoassay method provided the same reliability to ELISA in terms of the diagnostic accuracy for current H. pylori infection, although we should take into account the titer value differences by each test method in practical use.

2.
Helicobacter ; 24(3): e12575, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30873719

RESUMO

BACKGROUND: Metronidazole is an antiprotozoal drug used to treat a broad spectrum of infectious diseases, including Helicobacter pylori (H pylori) infections. In Japan, metronidazole is approved for the eradication therapy of H pylori as a second-line regimen among adults, but it has not yet been approved for use among children and adolescents. MATERIALS AND METHODS: To perform this narrative review, we searched the relevant literature on important events in the history of the use of metronidazole, its mechanisms of action, its efficacy, and the adverse effects reported in clinical trials or cohort studies in Japan. RESULTS: At present, metronidazole resistance has not been a serious issue in Japan in large part due to its restricted use. Emerging evidence from randomized controlled trials demonstrates higher eradication rates for metronidazole than for clarithromycin, supporting its use in both first-line and second-line eradication therapies. Among the reported adverse effects, there has been lingering concern over the potential carcinogenicity of metronidazole in humans. However, the possibility of an increased cancer risk is not limited to metronidazole; the long-term use of antibiotics has been linked to increased risk for some site-specific cancers. However, recent prospective studies have suggested that short-term exposure to antibiotics is not associated with an increased cancer risk. CONCLUSION: Sensible use of metronidazole backed by research evidence could maximize the benefits associated with H pylori eradication in Japan.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Metronidazol/uso terapêutico , Adolescente , Criança , Erradicação de Doenças , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/prevenção & controle , Humanos , Japão
3.
Sleep ; 42(6)2019 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-30810208

RESUMO

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 have been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31 230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (p-value < 5.0 × 10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5140 Japanese individuals (p-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2. Our study has confirmed that a functional ALDH2 variant, rs671, most strongly influences on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.

4.
Nucleic Acids Res ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30335158

RESUMO

Histone 3 lysine 4 (H3K4) methyltransferases MLL3 and MLL4 (MLL3/4) are required for enhancer activation during cell differentiation, though the mechanism is incompletely understood. We have attempted to address this issue by generating two mouse lines: one expressing H3.3K4M, a lysine-4-to-methionine (K4M) mutation of histone H3.3 that inhibits H3K4 methylation, and the other carrying conditional double knockout of MLL3/4 enzymatic SET domain. Expression of H3.3K4M in lineage-specific precursor cells depletes H3K4 methylation and impairs adipose tissue and muscle development. Mechanistically, H3.3K4M prevents enhancer activation in adipogenesis by destabilizing MLL3/4 proteins but not other Set1-like H3K4 methyltransferases MLL1, MLL2, SET1A and SET1B. Notably, deletion of the enzymatic SET domain in lineage-specific precursor cells mimics H3.3K4M expression, destabilizes MLL3/4 proteins, and prevents adipose tissue and muscle development. Interestingly, destabilization of MLL3/4 by H3.3K4M in adipocytes does not affect adipose tissue maintenance and thermogenic function. Together, our findings indicate that expression of H3.3K4M, or deletion of the enzymatic SET domain, destabilizes enhancer H3K4 methyltransferases MLL3/4 and impairs adipose tissue and muscle development.

6.
PLoS One ; 13(9): e0203386, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30192808

RESUMO

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60-0.66) or 0.61 (0.58-0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42-0.91) and 1.98 (1.42-2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.

7.
Nano Lett ; 2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30075074

RESUMO

The electron transport layer (ETL) plays an important role in determining the device efficiency of organic solar cells (OSCs). A rational design of an ETL for OSCs targets high charge extraction and induction of an optimized active layer morphology. In this Letter, a high mobility In2O3 synthesized via a solution-processed combustion reaction is successfully used as a universal ETL in an organic photovoltaic device. With the modification of a thin layer of polyethylenimine ethoxylated (PEIE), a device based on crystalline In2O3 outperforms its counterpart, ZnO, in both PBDTTT-EFT-based fullerene and nonfullerene systems. As ZnO is replaced by In2O3, the average efficiency increases from 9.5% to 10.5% for PBDTTT-EFT-PC71BM fullerene-based organic solar cells and also increases from 10.8% to 11.5% for PBDTTT-EFT-IEICO-4F nonfullerene-based organic solar cells, respectively. Morphological studies have unraveled the fact that the crystalline In2O3 ETL with highly aligned nanocrystallites has induced the crystallization of polymer into a preferential molecular packing that favors the charge transport across an active layer. From the photophysical study, it is found that charge extraction in the crystalline In2O3 device is significantly faster than in the ZnO device due to the higher mobility of In2O3 and optimized nanomorphology of the active layer.

8.
J Clin Invest ; 128(7): 3144-3159, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29911994

RESUMO

Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3, but a role for JMJD3 in metabolic regulation has not been described. SIRT1 deacetylase maintains energy balance during fasting by directly activating both hepatic gluconeogenic and mitochondrial fatty acid ß-oxidation genes, but the underlying epigenetic and gene-specific mechanisms remain unclear. In this study, JMJD3 was identified unexpectedly as a gene-specific transcriptional partner of SIRT1 and epigenetically activated mitochondrial ß-oxidation, but not gluconeogenic, genes during fasting. Mechanistically, JMJD3, together with SIRT1 and the nuclear receptor PPARα, formed a positive autoregulatory loop upon fasting-activated PKA signaling and epigenetically activated ß-oxidation-promoting genes, including Fgf21, Cpt1a, and Mcad. Liver-specific downregulation of JMJD3 resulted in intrinsic defects in ß-oxidation, which contributed to hepatosteatosis as well as glucose and insulin intolerance. Remarkably, the lipid-lowering effects by JMJD3 or SIRT1 in diet-induced obese mice were mutually interdependent. JMJD3 histone demethylase may serve as an epigenetic drug target for obesity, hepatosteatosis, and type 2 diabetes that allows selective lowering of lipid levels without increasing glucose levels.

9.
Adv Mater ; 30(28): e1801501, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29782685

RESUMO

Incorporating narrow-bandgap near-infrared absorbers as the third component in a donor/acceptor binary blend is a new strategy to improve the power conversion efficiency (PCE) of organic photovoltaics (OPV). However, there are two main restrictions: potential charge recombination in the narrow-gap material and miscompatibility between each component. The optimized design is to employ a third component (structurally similar to the donor or acceptor) with a lowest unoccupied molecular orbital (LUMO) energy level similar to the acceptor and a highest occupied molecular orbital (HOMO) energy level similar to the donor. In this design, enhanced absorption of the active layer and enhanced charge transfer can be realized without breaking the optimized morphology of the active layer. Herein, in order to realize this design, two new narrow-bandgap nonfullerene acceptors with suitable energy levels and chemical structures are designed, synthesized, and employed as the third component in the donor/acceptor binary blend, which boosts the PCE of OPV to 11.6%.

11.
Cell Res ; 28(2): 204-220, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29313530

RESUMO

Long-range chromatin interactions between enhancers and promoters are essential for transcription of many developmentally controlled genes in mammals and other metazoans. Currently, the exact mechanisms that connect distal enhancers to their specific target promoters remain to be fully elucidated. Here, we show that the enhancer-specific histone H3 lysine 4 monomethylation (H3K4me1) and the histone methyltransferases MLL3 and MLL4 (MLL3/4) play an active role in this process. We demonstrate that in differentiating mouse embryonic stem cells, MLL3/4-dependent deposition of H3K4me1 at enhancers correlates with increased levels of chromatin interactions, whereas loss of this histone modification leads to reduced levels of chromatin interactions and defects in gene activation during differentiation. H3K4me1 facilitates recruitment of the Cohesin complex, a known regulator of chromatin organization, to chromatin in vitro and in vivo, providing a potential mechanism for MLL3/4 to promote chromatin interactions between enhancers and promoters. Taken together, our results support a role for MLL3/4-dependent H3K4me1 in orchestrating long-range chromatin interactions at enhancers in mammalian cells.

12.
Nat Genet ; 50(1): 73-82, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29255264

RESUMO

Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell-type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1-associated proteins, including many involved in chromatin remodeling. We demonstrate that H3K4me1 augments association of the chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro, H3K4me1-marked nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of the BAF component BAF45C indicate that monomethylation, but not trimethylation, is accommodated by BAF45C's H3K4-binding site. Our results suggest that H3K4me1 has an active role at enhancers by facilitating binding of the BAF complex and possibly other chromatin regulators.

13.
Sci Rep ; 7(1): 15491, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29138514

RESUMO

Changing trends in the prevalence of H. pylori infection in the general population over time are thought to be the main driving force behind the declining gastric cancer mortality in Japan. However, whether the prevalence of H. pylori infection itself shows a birth-cohort pattern needs to be corroborated. We performed a systematic review of studies that reported the prevalence of H. pylori infection among Japanese individuals. Meta-regression was conducted in the framework of a generalized additive mixed model (GAMM) to account for heterogeneity in the prevalence of H. pylori infection as a function of birth year. The prevalence of H. pylori infection confirmed a clear birth cohort pattern: the predicted prevalence (%, 95% CI) was 60.9 (56.3-65.4), 65.9 (63.9-67.9), 67.4 (66.0-68.7), 64.1 (63.1-65.1), 59.1 (58.2-60.0), 49.1 (49.0-49.2), 34.9 (34.0-35.8), 24.6 (23.5-25.8), 15.6 (14.0-17.3), and 6.6 (4.8-8.9) among those who were born in the year 1910, 1920, 1930, 1940, 1950, 1960, 1970, 1980, 1990, and 2000, respectively. The present study demonstrated a clear birth-cohort pattern of H. pylori infection in the Japanese population. The decreased prevalence of H. pylori infection in successive generations should be weighed in future gastric cancer control programs.

14.
Proc Natl Acad Sci U S A ; 114(43): E9046-E9055, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29073101

RESUMO

Kabuki syndrome, a congenital craniofacial disorder, manifests from mutations in an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A) or a H3 lysine 4 methylase (KMT2D). However, the cellular and molecular etiology of histone-modifying enzymes in craniofacial disorders is unknown. We now establish Kabuki syndrome as a neurocristopathy, whereby the majority of clinical features are modeled in mice carrying neural crest (NC) deletion of UTX, including craniofacial dysmorphism, cardiac defects, and postnatal growth retardation. Female UTX NC knockout (FKO) demonstrates enhanced phenotypic severity over males (MKOs), due to partial redundancy with UTY, a Y-chromosome demethylase-dead homolog. Thus, NC cells may require demethylase-independent UTX activity. Consistently, Kabuki causative point mutations upstream of the JmjC domain do not disrupt UTX demethylation. We have isolated primary NC cells at a phenocritical postmigratory timepoint in both FKO and MKO mice, and genome-wide expression and histone profiling have revealed UTX molecular function in establishing appropriate chromatin structure to regulate crucial NC stem-cell signaling pathways. However, the majority of UTX regulated genes do not experience aberrations in H3K27me3 or H3K4me3, implicating alternative roles for UTX in transcriptional control. These findings are substantiated through demethylase-dead knockin mutation of UTX, which supports appropriate facial development.


Assuntos
Anormalidades Múltiplas/etiologia , Face/anormalidades , Doenças Hematológicas/etiologia , Histona Desmetilases/metabolismo , Crista Neural/fisiopatologia , Doenças Vestibulares/etiologia , Animais , Sobrevivência Celular/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Histona Desmetilases/genética , Humanos , Lisina/metabolismo , Masculino , Camundongos Knockout , Camundongos Transgênicos , Mutação , Crista Neural/metabolismo , Proteínas Nucleares/genética , Crânio/embriologia
15.
Nat Immunol ; 18(9): 1035-1045, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28759003

RESUMO

MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.


Assuntos
Diferenciação Celular/genética , Cromatina/metabolismo , Fatores de Transcrição Forkhead/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Linfócitos T Reguladores , Animais , Sistemas CRISPR-Cas , Citocinas/imunologia , Citometria de Fluxo , Regulação da Expressão Gênica , Immunoblotting , Técnicas In Vitro , Metilação , Camundongos
16.
Nat Commun ; 8: 15464, 2017 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-28561021

RESUMO

Although CRISPR/Cas9 genome editing has provided numerous opportunities to interrogate the functional significance of any given genomic site, there is a paucity of data on the extent of molecular scars inflicted on the mouse genome. Here we interrogate the molecular consequences of CRISPR/Cas9-mediated deletions at 17 sites in four loci of the mouse genome. We sequence targeted sites in 632 founder mice and analyse 54 established lines. While the median deletion size using single sgRNAs is 9 bp, we also obtain large deletions of up to 600 bp. Furthermore, we show unreported asymmetric deletions and large insertions of middle repetitive sequences. Simultaneous targeting of distant loci results in the removal of the intervening sequences. Reliable deletion of juxtaposed sites is only achieved through two-step targeting. Our findings also demonstrate that an extended analysis of F1 genotypes is required to obtain conclusive information on the exact molecular consequences of targeting events.


Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Genoma/genética , Deleção de Sequência/genética , Animais , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Guia/genética
17.
Cell Biosci ; 7: 25, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28529687

RESUMO

BACKGROUND: Natural killer (NK)T cells and conventional T cells share phenotypic characteristic however they differ in transcription factor requirements and functional properties. The role of histone modifying enzymes in conventional T cell development has been extensively studied, little is known about the function of enzymes regulating histone methylation in NKT cells. RESULTS: We show that conditional deletion of histone demethylases UTX and JMJD3 by CD4-Cre leads to near complete loss of liver NKT cells, while conventional T cells are less affected. Loss of NKT cells is cell intrinsic and not due to an insufficient selection environment. The absence of NKT cells in UTX/JMJD3-deficient mice protects mice from concanavalin A-induced liver injury, a model of NKT-mediated hepatitis. GO-analysis of RNA-seq data indicates that cell cycle genes are downregulated in UTX/JMJD3-deleted NKT progenitors, and suggest that failed expansion may account for some of the cellular deficiency. The phenotype appears to be demethylase-dependent, because UTY, a homolog of UTX that lacks catalytic function, is not sufficient to restore their development and removal of H3K27me3 by deletion of EZH2 partially rescues the defect. CONCLUSIONS: NKT cell development and gene expression is sensitive to proper regulation of H3K27 methylation. The H3K27me3 demethylase enzymes, in particular UTX, promote NKT cell development, and are required for effective NKT function.

18.
Asia Pac J Public Health ; 29(4): 278-287, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28417677

RESUMO

The rise of noncommunicable diseases is a serious health burden for Palau. This study described the prevalence of hypertension, and assessed its association with obesity. Surveys following the WHO STEPwise approach to surveillance were conducted in 2529 adults. Multivariate prevalence ratios (PR) of hypertension for body mass index (BMI) categories were calculated by logistic regression models using conditional standardization procedure. Age- and sex-specified analyses were performed. Overall prevalence of obesity and hypertension were 40.4% and 46.8%, respectively. Prevalence of hypertension was positively associated with BMI. However, overweight men had as high prevalence of hypertension as the obese (multivariable-adjusted PR was 1.84 for overweight and 1.91 for obese compared with nonoverweight). The association between hypertension and BMI was similar across age groups. The prevalence of hypertension in women increased gradually with the increase of BMI whereas that in men reached a plateau already in the overweight.


Assuntos
Hipertensão/epidemiologia , Obesidade/epidemiologia , Vigilância da População/métodos , Adulto , Feminino , Inquéritos Epidemiológicos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Palau/epidemiologia , Prevalência , Distribuição por Sexo , Organização Mundial da Saúde
19.
Orphanet J Rare Dis ; 12(1): 62, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28351420

RESUMO

Chronic intestinal pseudo-obstruction (CIPO) is a rare intestinal motility disorder with significant morbidity and mortality in pediatric patients. The diagnosis of CIPO is difficult, because it is clinically based on the symptoms and signs of bowel obstruction which are similar to the clinical manifestations of other gastrointestinal diseases like short bowel syndrome (SBS). Therefore, it is desirable to identify and establish new laboratory diagnostic markers for CIPO that are reliable and easily accessible. In our study we have identified the ratio of the urinary glutamine and glutamic acid as a promising biomarker for distinguishing suspected CIPO cases and simple SBS cases. The area under ROC curve was 0.83, at cutoff value = 7.04 with sensitivity of 65% and specificity of 92%.


Assuntos
Biomarcadores/urina , Glutamatos/urina , Glutamina/urina , Pseudo-Obstrução Intestinal/urina , Adolescente , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Lactente , Masculino , Sensibilidade e Especificidade
20.
Nucleic Acids Res ; 45(8): 4606-4618, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28334928

RESUMO

The zinc finger protein CTCF has been invoked in establishing boundaries between genes, thereby controlling spatial and temporal enhancer activities. However, there is limited genetic evidence to support the concept that these boundaries restrict the search space of enhancers. We have addressed this question in the casein locus containing five mammary and two non-mammary genes under the control of at least seven putative enhancers. We have identified two CTCF binding sites flanking the locus and two associated with a super-enhancer. Individual deletion of these sites from the mouse genome did not alter expression of any of the genes. However, deletion of the border CTCF site separating the Csn1s1 mammary enhancer from neighboring genes resulted in the activation of Sult1d1 at a distance of more than 95 kb but not the more proximal and silent Sult1e1 gene. Loss of this CTCF site led to de novo interactions between the Sult1d1 promoter and several enhancers in the casein locus. Our study demonstrates that only one out of the four CTCF sites in the casein locus had a measurable in vivo activity. Studies on additional loci are needed to determine the biological role of CTCF sites associated with enhancers.


Assuntos
Sistemas CRISPR-Cas , Citocinas/genética , Elementos Facilitadores Genéticos , Loci Gênicos , Genoma , Proteínas Repressoras/genética , Animais , Sítios de Ligação , Fator de Ligação a CCCTC , Caseínas/genética , Caseínas/metabolismo , Citocinas/metabolismo , Feminino , Edição de Genes , Regulação da Expressão Gênica , Glândulas Mamárias Animais/metabolismo , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Repressoras/metabolismo , Sulfotransferases/genética , Sulfotransferases/metabolismo
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