Transgenerational epigenetic inheritance in mammals remains a debated subject. Here, we demonstrate that DNA methylation of promoter-associated CpG islands (CGIs) can be transmitted from parents to ...their offspring in mice. We generated DNA methylation-edited mouse embryonic stem cells (ESCs), in which CGIs of two metabolism-related genes, the Ankyrin repeat domain 26 and the low-density lipoprotein receptor, were specifically methylated and silenced. DNA methylation-edited mice generated by microinjection of the methylated ESCs exhibited abnormal metabolic phenotypes. Acquired methylation of the targeted CGI and the phenotypic traits were maintained and transmitted across multiple generations. The heritable CGI methylation was subjected to reprogramming in parental PGCs and subsequently reestablished in the next generation at post-implantation stages. These observations provide a concrete step toward demonstrating transgenerational epigenetic inheritance in mammals, which may have implications in our understanding of evolutionary biology as well as the etiology, diagnosis, and prevention of non-genetically inherited human diseases.
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•Establishment of targeted CGI methylation editing in mouse ES cells•DNA methylation-edited mice exhibit phenotypic alterations induced by gene silencing•Both acquired methylation and phenotypes are transmitted across multiple generations•Heritable epigenetic memory reestablishes CGI methylation at the epiblast stage
Takahashi et al. demonstrate that engineered epigenetic modifications and associated phenotypes can be transmitted across multiple generations in mammals.
The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized ...niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited, and disrupting this critical developmental transition remains a long-standing goal. Here we show that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as probable targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci prone to spontaneous activation. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first discovery of a transcriptional switch controlling a differentiation decision in protozoan parasites.
Clinicians supporting patients in lifestyle behavior change is an important strategy to help reduce chronic disease burden. Using National Health and Nutrition Examination Survey (NHANES) data from ...2015 to 2018, this study assessed rates of and associations between patient-reported receipt of lifestyle behavior change advice and corresponding self-reported behavior change for four different lifestyle behaviors: 1) weight loss, 2) increase physical activity, 3) reduce sodium, and 4) reduce fat and calories. Adult survey respondents with hypertension and/or diabetes (n = 4716) who received lifestyle advice ranged from 43% to 58%, with the most common recommendation being to increase physical activity. Between 61% and 73% of respondents reported currently modifying health behaviors, with the greatest number reporting weight loss. Multiple logistic regression models were used to test associations for each lifestyle behavior advice-behavior change pair, adjusting for demographic characteristics. Compared to those who received no advice, respondents who received advice had significantly higher odds of reporting losing weight (aOR: 1.93; 95% CI: 1.51, 2.48); increasing physical activity (aOR 2.02; 95% CI: 1.73, 2.37); reducing dietary sodium (aOR 4.95; 95% CI: 3.93, 6.25); and reducing intake of fat/cal (aOR 3.57; 95% CI: 2.86, 4.45). This study utilized population level data to lend further evidence that provider advice about lifestyle behaviors for patients who have hypertension or diabetes may influence patient behavior. However, prevalence of advice is low, and differences in rates of behavior change exist across socioeconomic status and race/ethnicity, indicating a need to further research how providers might better support patients with varying social needs.
•Reported advice from providers is associated with behavior changes amongst US adults with hypertension and/or diabetes.•Those who report receiving advice to reduce sodium have higher odds of doing so compared to other types of advice.•Patient income is a significant predictor of reported lifestyle behavior changes.
The biology and behavior of adults differ substantially from those of developing animals, and cell-specific information is critical for deciphering the biology of multicellular animals. Thus, adult ...tissue-specific transcriptomic data are critical for understanding molecular mechanisms that control their phenotypes. We used adult cell-specific isolation to identify the transcriptomes of C. elegans' four major tissues (or "tissue-ome"), identifying ubiquitously expressed and tissue-specific "enriched" genes. These data newly reveal the hypodermis' metabolic character, suggest potential worm-human tissue orthologies, and identify tissue-specific changes in the Insulin/IGF-1 signaling pathway. Tissue-specific alternative splicing analysis identified a large set of collagen isoforms. Finally, we developed a machine learning-based prediction tool for 76 sub-tissue cell types, which we used to predict cellular expression differences in IIS/FOXO signaling, stage-specific TGF-β activity, and basal vs. memory-induced CREB transcription. Together, these data provide a rich resource for understanding the biology governing multicellular adult animals.
There has been a steady increase in cannabis use among US adolescents over the past decade. Perceptions of risk, specifically the belief that cannabis use is not harmful, may contribute to this ...increased use. The purpose of this study was to evaluate parental, school, and peer influence as protective factors in perceiving there is risk of harm from monthly cannabis use. Using the 2017 National Survey on Drug Use and Health (NSDUH), the study outcome was self-reported perceived risk of harm from monthly cannabis use amongst adolescents between ages 12 and 17. The exposures were parental monitoring and support, perception of school importance, extracurricular activity participation, peer attitudes towards cannabis use, and perception of peer cannabis use. Of 12,024 eligible adolescents, about 80% reported perceived risk of harm from monthly cannabis use. Multiple logistic regression models suggest the perception of risk of harm from monthly cannabis use was significantly associated with perception of peers using cannabis, perception of peers’ disapproval of cannabis use, perception of school importance, and participation in extracurricular activities. Adolescents who perceived that monthly cannabis use was risky had high parental monitoring, low perception of peer use, high perception of peers’ disapproval of cannabis use, high perception of school importance, and participated more in extracurricular activities. These findings suggest substance use prevention programs targeting adolescent attitudes and beliefs would benefit from leveraging peer influence, promoting extracurricular activities, and enhancing schoolwork to be more meaningful.
Mutations in the LKB1 (also known as
) tumor suppressor are the third most frequent genetic alteration in non-small cell lung cancer (NSCLC).
encodes a serine/threonine kinase that directly ...phosphorylates and activates 14 AMPK family kinases ("AMPKRs"). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of
revealed increased tumor growth in mouse models of
-dependent lung cancer, which was further enhanced by loss of the related kinase
. As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss. SIGNIFICANCE: The tumor suppressor
encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer.
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Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible ...for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.
Clinical events suggestive of nutrition care found in electronic health records (EHRs) are rarely explored for their associations with hypertension outcomes.
Longitudinal analysis using structured ...EHR data from primary care visits at a health system in the US from December 2017-December 2020 of adult patients with hypertension (n = 4,237) tested for associations between last visit blood pressure (BP) control (≤ 140 Systolic BP and ≤ 90 Diastolic BP) and ≥ 1 nutrition care clinical event operationalized as (overweight or obesity (BMI > 25 or 30, respectively) diagnoses, preventive care visits, or provision of patient education materials (PEM)). Descriptive statistics and longitudinal targeted maximum likelihood estimation (LTMLE) models were conducted to explore average treatment effects (ATE) of timing and dose response from these clinical events on blood pressure control overall and by race.
The median age was 62 years, 29% were male, 52% were Black, 25% were from rural areas and 50% had controlled BP at baseline. Annual documentation of overweight/obesity diagnoses ranged 3.0-7.8%, preventive care visits ranged 6.2-15.7%, and PEM with dietary and hypertension content were distributed to 8.5-28.8% patients. LTMLE models stratified by race showed differences in timing, dose, and type of nutrition care. Black patients who had nutrition care in Year 3 only compared to none had lower odds for BP control (ATE -0.23, 95% CI: -0.38,-0.08, p = 0.003), preventive visits in the last 2 years high higher odds for BP control (ATE 0.31, 95% CI: 0.07,0.54, p = 0.01), and early or late PEMs had lower odds for BP control (ATE -0.08, 95% CI: -0.15,-0.01, p = 0.03 and ATE -0.23, 95% CI: -0.41,-0.05, p = 0.01, respectively).
In this study, clinical events suggestive of nutrition care are significantly associated with BP control, but are infrequent and effects differ by type, timing, and patient race. Preventive visits appear to have the most effect; additional research should include examining clinical notes for evidence of nutrition care among different populations, which may uncover areas for improving nutrition care for patients with chronic disease.
Malaria afflicts over 200 million people worldwide, and its most lethal etiologic agent, Plasmodium falciparum, is evolving to resist even the latest-generation therapeutics. Efficient tools for ...genome-directed investigations of P. falciparum-induced pathogenesis, including drug-resistance mechanisms, are clearly required. Here we report rapid and targeted genetic engineering of this parasite using zinc-finger nucleases (ZFNs) that produce a double-strand break in a user-defined locus and trigger homology-directed repair. Targeting an integrated egfp locus, we obtained gene-deletion parasites with unprecedented speed (2 weeks), both with and without direct selection. ZFNs engineered against the parasite gene pfcrt, responsible for escape under chloroquine treatment, rapidly produced parasites that carried either an allelic replacement or a panel of specified point mutations. This method will enable a diverse array of genome-editing approaches to interrogate this human pathogen.
Highlights ► Small, fast steps are known to precede freezing of gait in Parkinson disease (PD). ► We asked how step length and/or cadence manipulation impacts gait coordination. ► We compared four ...groups: PD with and without freezing, and old and young controls. ► Taking small or small, fast steps worsened coordination in PD, particularly those with freezing. ► Taking small, fast or small and fast steps did not elicit any freezing episodes.
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