Non-CG methylation patterns shape the epigenetic landscape in Arabidopsis.

DNA methylation occurs in CG and non-CG sequence contexts. Non-CG methylation is abundant in plants and is mediated by CHROMOMETHYLASE (CMT) and DOMAINS REARRANGED METHYLTRANSFERASE (DRM) proteins; however, its roles remain poorly understood. Here we characterize the roles of non-CG methylation in Arabidopsis thaliana. We show that a poorly characterized methyltransferase, CMT2, is a functional methyltransferase in vitro and in vivo. CMT2 preferentially binds histone H3 Lys9 (H3K9) dimethylation and methylates non-CG cytosines that are regulated by H3K9 methylation. We revealed the contributions and redundancies between each non-CG methyltransferase in DNA methylation patterning and in regulating transcription. We also demonstrate extensive dependencies of small-RNA accumulation and H3K9 methylation patterning on non-CG methylation, suggesting self-reinforcing mechanisms between these epigenetic factors. The results suggest that non-CG methylation patterns are critical in shaping the landscapes of histone modification and small noncoding RNA

Gerald J. Wasserburg Awarded 2008 William Bowie Medal

Gerald J. Wasserburg was awarded the 2008 William Bowie Medal at the AGU Fall Meeting Honors Ceremony, held 17 December 2008 in San Francisco, Calif. The medal is for “outstanding contributions to fundamental geophysics and for unselfish cooperation in research.

Targeted DNA demethylation of the Arabidopsis genome using the human TET1 catalytic domain.

DNA methylation is an important epigenetic modification involved in gene regulation and transposable element silencing. Changes in DNA methylation can be heritable and, thus, can lead to the formation of stable epialleles. A well-characterized example of a stable epiallele in plants is fwa, which consists of the loss of DNA cytosine methylation (5mC) in the promoter of the FLOWERING WAGENINGEN (FWA) gene, causing up-regulation of FWA and a heritable late-flowering phenotype. Here we demonstrate that a fusion between the catalytic domain of the human demethylase TEN-ELEVEN TRANSLOCATION1 (TET1cd) and an artificial zinc finger (ZF) designed to target the FWA promoter can cause highly efficient targeted demethylation, FWA up-regulation, and a heritable late-flowering phenotype. Additional ZF-TET1cd fusions designed to target methylated regions of the CACTA1 transposon also caused targeted demethylation and changes in expression. Finally, we have developed a CRISPR/dCas9-based targeted demethylation system using the TET1cd and a modified SunTag system. Similar to the ZF-TET1cd fusions, the SunTag-TET1cd system is able to target demethylation and activate gene expression when directed to the FWA or CACTA1 loci. Our study provides tools for targeted removal of 5mC at specific loci in the genome with high specificity and minimal off-target effects. These tools provide the opportunity to develop new epialleles for traits of interest, and to reactivate expression of previously silenced genes, transgenes, or transposons

TFAP2C regulates transcription in human naive pluripotency by opening enhancers.

Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse

The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men

The association between benign prostatic hyperplasia and chronic kidney disease in community-dwelling men.BackgroundBenign prostatic hyperplasia (BPH) and chronic kidney disease are important public health problems in older men. Previous referral-based studies disagree on whether BPH is associated with chronic kidney disease. The objective of this study was to determine the community-based association between clinical measures of BPH and chronic kidney disease.MethodsA community-based sample of 2115 white men (ages 40–79 years) was randomly selected from the Olmsted County, Minnesota population (55% participation rate) in 1990. A random subsample (N = 476) had a detailed clinical evaluation. This evaluation included a questionnaire with similar queries to the International Prostate Symptom Score (IPSS), peak urinary flow rates (uroflowmeter), postvoid residual urine volume (ultrasound), prostate volume (ultrasound), serum prostate specific antigen (PSA), and serum creatinine.ResultsAfter adjustment for age, hypertension, diabetes, leukocyte esterase positive (possible urinary tract infection), and smoking, chronic kidney disease [serum creatinine ≥133 μmol/L (1.5 mg/dL)] was associated with diminished peak urinary flow rate (<15 mL/sec) by an odds ratio (OR) = 2.96 (95% CI 1.30–7.01), moderate-severe lower urinary tract symptoms (IPSS >7) by an OR = 2.91 (95% CI 1.32–6.62), and chronic urinary retention (postvoid residual >100 mL) by an OR = 2.28 (95% CI 0.66–6.68). There was no association with a prostate volume >30 mL by an OR = 0.56 (95% CI 0.22–1.37) or PSA >1.4 ng/mL by an OR = 1.17 (95% CI 0.47–2.81).ConclusionThere was a cross-sectional association between signs and symptoms of bladder outlet obstruction and chronic kidney disease in community-dwelling men. Prostatic enlargement was not associated with chronic kidney disease

Use of echocardiography in the management of congestive heart failure in the community

AbstractObjectives. We evaluated the use and the impact of echocardiography in patients receiving an initial diagnosis of congestive heart failure in Olmsted County, Minnesota, in 1991.Background. The American College of Cardiology/American Heart Association clinical practice guidelines recommend echocardiography in all patients with suspected congestive heart failure. No data are available on use and impact of echocardiography in management of congestive heart failure in a community.Methods. The medical records linkage system of the Rochester Epidemiology Project was used to identify all 216 patients who satisfied the Framingham criteria for congestive heart failure. Of these, 137 (63%) underwent echocardiography within 3 weeks before or after the episode of congestive heart failure (Echo group), and the other 79 patients constitute the No-Echo group.Results. The No-Echo group patients were older (p = 0.022), were more likely to be female (p = 0.072), had milder symptoms (p = 0.001) and were less often hospitalized at diagnosis (p = 0.001). Fewer patients in the No-Echo group were treated with angiotensin-converting enzyme inhibitors (p = 0.001). Advanced age (≥80 years), lower New York Heart Association functional class, absence of a fourth heart sound on examination, absence of cardiomegaly or signs of congestive heart failure on chest radiography and absence of known valve disease were independently related to the decision not to obtain an echocardiogram. Survival after adjustment for age, functional class and gender was lower in the No-Echo group than the Echo group (risk ratio = 0.607, p = 0.017).Conclusions. The underuse of echocardiography appears to be associated with poorer survival and underuse of angiotensin-converting enzyme inhibitor therapy

Diastolic dysfunction and left atrial volume A population-based study

ObjectivesWe examined the association between diastolic function and left atrial volume indexed to body surface area (LAVi) in a population-based study.BackgroundAtrial enlargement has been suggested as a marker of the severity and duration of diastolic dysfunction (DD). However, the association between DD and atrial enlargement and their individual prognostic implications in the population is poorly defined.MethodsA cross-sectional sample of Olmsted County, Minnesota, residents ≥45 years of age (n = 2,042) underwent comprehensive Doppler echocardiography and medical record review.ResultsThe LAVi increased with worsening DD: 23 ± 6 ml/m2(normal), 25 ± 8 ml/m2(grade I DD), 31 ± 8 ml/m2(grade II DD), 48 ± 12 ml/m2(grades III to IV DD). In bivariate analyses, age, left ventricular mass index, and DD grade were positively associated, whereas female gender and ejection fraction (EF) were inversely associated with LAVi (p < 0.001 for all). When controlling for age, gender, cardiovascular (CV) disease, EF, and left ventricular mass, grade II DD was associated with a 24%, and grade III to IV DD was associated with a 62% larger LA volume (p < 0.0001 for both). The area under the receiver-operator characteristic curve for LAVi to detect grade I, grade II, or grade III to IV DD was 0.57, 0.81, and 0.98, respectively. Both DD and LAVi were predictive of all-cause mortality, but when controlling for DD, LAVi was not an independent predictor of mortality.ConclusionsThese data suggest that DD contributes to LA remodeling. Indeed, DD is a stronger predictor of mortality; presumably it better reflects the impact of CV disease within the general population

Progression and treatment of incident lower urinary tract symptoms ( LUTS ) among men in the C alifornia M en's H ealth S tudy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110063/1/bju12810.pd