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The PIWI protein MIWI2 and its associated PIWI-interacting RNAs (piRNAs) instruct DNA methylation of young active transposable elements (TEs) in the male germline. piRNAs are proposed to recruit MIWI2 to the transcriptionally active TE loci by base pairing to nascent transcripts, however the downstream mechanisms and effector proteins utilized by MIWI2 in directing de novo TE methylation remain incompletely understood. Here, we show that MIWI2 associates with TEX15 in foetal gonocytes. TEX15 is predominantly a nuclear protein that is not required for piRNA biogenesis but is essential for piRNA-directed TE de novo methylation and silencing. In summary, TEX15 is an essential executor of mammalian piRNA-directed DNA methylation. The PIWI protein MIWI2 counteracts transposon activity by transcriptional silencing in the mammalian germline. Here, the authors show that TEX15 interacts with MIWI2 and is required for piRNA-directed methylation of transposable elements in male germ cells.

The PIWI-interacting RNA (piRNA) pathway guides the DNA methylation of young, active transposons during germline development in male mice 1 . piRNAs tether the PIWI protein MIWI2 (PIWIL4) to the nascent transposon transcript, resulting in DNA methylation through SPOCD1 (refs. 2 – 5 ). Transposon methylation requires great precision: every copy needs to be methylated but off-target methylation must be avoided. However, the underlying mechanisms that ensure this precision remain unknown. Here, we show that SPOCD1 interacts directly with SPIN1 (SPINDLIN1), a chromatin reader that primarily binds to H3K4me3-K9me3 (ref. 6 ). The prevailing assumption is that all the molecular events required for piRNA-directed DNA methylation occur after the engagement of MIWI2. We find that SPIN1 expression precedes that of both SPOCD1 and MIWI2. Furthermore, we demonstrate that young LINE1 copies, but not old ones, are marked by H3K4me3, H3K9me3 and SPIN1 before the initiation of piRNA-directed DNA methylation. We generated a Spocd1 separation-of-function allele in the mouse that encodes a SPOCD1 variant that no longer interacts with SPIN1. We found that the interaction between SPOCD1 and SPIN1 is essential for spermatogenesis and piRNA-directed DNA methylation of young LINE1 elements. We propose that piRNA-directed LINE1 DNA methylation requires a developmentally timed two-factor authentication process. The first authentication is the recruitment of SPIN1–SPOCD1 to the young LINE1 promoter, and the second is MIWI2 engagement with the nascent transcript. In summary, independent authentication events underpin the precision of piRNA-directed LINE1 DNA methylation. In male mouse germline development, the precise DNA methylation of young, active transposons requires a two-step process in which SPIN1 and SPOCD1 mark young LINE1 elements before the piRNA pathway triggers DNA methylation.

In mammals, the acquisition of the germline from the soma provides the germline with an essential challenge: the need to erase and reset genomic methylation 1 . In the male germline, RNA-directed DNA methylation silences young, active transposable elements 2 – 4 . The PIWI protein MIWI2 (PIWIL4) and its associated PIWI-interacting RNAs (piRNAs) instruct DNA methylation of transposable elements 3 , 5 . piRNAs are proposed to tether MIWI2 to nascent transposable element transcripts; however, the mechanism by which MIWI2 directs the de novo methylation of transposable elements is poorly understood, although central to the immortality of the germline. Here we define the interactome of MIWI2 in mouse fetal gonocytes undergoing de novo genome methylation and identify a previously unknown MIWI2-associated factor, SPOCD1, that is essential for the methylation and silencing of young transposable elements. The loss of Spocd1 in mice results in male-specific infertility but does not affect either piRNA biogenesis or the localization of MIWI2 to the nucleus. SPOCD1 is a nuclear protein whose expression is restricted to the period of de novo genome methylation. It co-purifies in vivo with DNMT3L and DNMT3A, components of the de novo methylation machinery, as well as with constituents of the NURD and BAF chromatin remodelling complexes. We propose a model whereby tethering of MIWI2 to a nascent transposable element transcript recruits repressive chromatin remodelling activities and the de novo methylation apparatus through SPOCD1. In summary, we have identified a previously unrecognized and essential executor of mammalian piRNA-directed DNA methylation. Newly identified protein SPOCD1 is crucial in de novo DNA methylation directed by PIWI proteins and piRNAs, helping to control DNA silencing in mouse male germline.

Several developmental stages of spermatogenesis are transcriptionally quiescent which presents major challenges associated with the regulation of gene expression. Here we identify that the zygotene to pachytene transition is not only associated with the resumption of transcription but also a wave of programmed mRNA degradation that is essential for meiotic progression. We explored whether terminal uridydyl transferase 4- (TUT4-) or TUT7-mediated 3′ mRNA uridylation contributes to this wave of mRNA degradation during pachynema. Indeed, both TUT4 and TUT7 are expressed throughout most of spermatogenesis, however, loss of either TUT4 or TUT7 does not have any major impact upon spermatogenesis. Combined TUT4 and TUT7 (TUT4/7) deficiency results in embryonic growth defects, while conditional gene targeting revealed an essential role for TUT4/7 in pachytene progression. Loss of TUT4/7 results in the reduction of miRNA, piRNA and mRNA 3′ uridylation. Although this reduction does not greatly alter miRNA or piRNA expression, TUT4/7-mediated uridylation is required for the clearance of many zygotene-expressed transcripts in pachytene cells. We find that TUT4/7-regulated transcripts in pachytene spermatocytes are characterized by having long 3′ UTRs with length-adjusted enrichment for AU-rich elements. We also observed these features in TUT4/7-regulated maternal transcripts whose dosage was recently shown to be essential for sculpting a functional maternal transcriptome and meiosis. Therefore, mRNA 3′ uridylation is a critical determinant of both male and female germline transcriptomes. In conclusion, we have identified a novel requirement for 3′ uridylation-programmed zygotene mRNA clearance in pachytene spermatocytes that is essential for male meiotic progression.

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1 / Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax.

Autophagy is an intracellular recycling system that contributes to the maintenance of cellular homeostasis. However, by providing tolerance to various stressors, autophagy promotes the survival and proliferation of cancer cells and confers resistance to chemotherapy. Anticancer drugs activate autophagy, leading to drug resistance in cancer cells. Autophagy inhibitors, such as chloroquine and hydroxychloroquine, enhance the antitumor effects of anticancer drugs when used in combination with them. However, these inhibitors are associated with several adverse effects. Here, using genome‐wide RNA sequencing analysis, we deciphered a novel function of electrolyzed hydrogen water (EHW) in suppressing autophagy by activating mammalian target of rapamycin complex 1 signalling. The combination of EHW with anticancer drugs, such as 5‐fluorouracil or paclitaxel, which activate autophagy, significantly decreased the viability of cervical and colorectal cancer cells. Mechanistically, molecular hydrogen and trace elements in EHW may suppress autophagy and potentiate anticancer effects. Considering its safety, we propose that EHW can act as a novel adjuvant to anticancer therapy.

The relationship between frailty and blood pressure (BP) is inconsistent, and limited research has compared BP by frailty status using long-term home BP measurements. We aimed to identify office and home BP and determine differences according to frailty status, stratified by taking antihypertensives in community-dwelling older adults. This cross-sectional study was part of the ongoing non-randomized intervention NOSE study. Participants were aged ≥ 64 years. Frailty was categorized robust, pre-frailty, or frailty using the revised Japanese version of the Cardiovascular Health Study criteria. Office BP was measured in survey settings, and each participant was instructed to take home BP. We used the average home BP for 4 weeks post-survey. An analysis of covariance analyzed the relationship between frailty and office and home BP, and their differences stratified by antihypertensive use. We included 418 older participants (mean age: 72.8 years); 39.5% were male, 40.4% were taking antihypertensives, and 6.7% had frailty. Individuals with frailty taking antihypertensives had higher home morning systolic BP (SBP) than those with robust (134.2 vs. 145.7 mmHg, P  = 0.018) and pre-frailty (135.6 vs. 145.7 mmHg, P  = 0.024). The difference between office and morning home SBP in treated participants was 7.1 mmHg (robust), 4.7 mmHg (pre-frailty), and −5.1 mmHg (frailty), showing significant differences (robust vs. frailty: P  = 0.005, pre-frailty vs. frailty: P  = 0.016). Home morning SBP was higher in individuals with frailty taking antihypertensives compared to those without frailty, and it may be higher than office BP. Individuals with frailty should measure home BP for good BP control.

Background A decline in cognitive function is associated with inflammatory processes. However, the association between high-sensitivity C-reactive protein (hs-CRP) levels and cognitive decline in the Japanese population remains inconclusive. Thus, this study aimed to determine whether hs-CRP is associated with low cognitive function in 70- and 80-year-old community-dwelling Japanese individuals. Methods The participants in this cross-sectional study were 872 Japanese residents aged 70 and 80 years who voluntarily participated in the Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians (SONIC) study between 2010 and 2011. Blood sample collection, cognitive assessment, and other measurements were performed at the venue. Low cognitive function was defined as a score of 25 points or lower on the Japanese version of the Montreal Cognitive Assessment. The odds ratio (OR) and 95% confidence interval (95% CI) for each hs-CRP quartile were calculated using logistic regression analysis. Results A total of 288 (69.9%) parsons in the 70-year-old group and 372 (80.9%) in the 80-year-old group exhibited low cognitive function. The association between hs-CRP levels and low cognitive function was significant among 70- and 80-year-old Japanese community-dwelling adults. In particular, the fourth quartile of hs-CRP (0.727–7.420 mg/L) in the 70-year-old group and the second and fourth quartiles (0.214–0.404 and 0.911–9.890 mg/L) in the 80-year-old group were associated with low cognitive function. Furthermore, the third quartile (0.409–0.892 mg/L) in the 80-year-old group was closely associated with low cognitive function. Conclusions High hs-CRP levels were associated with lower cognitive function in 70- and 80-year-old Japanese community-dwelling individuals, suggesting that high hs-CRP levels may influence cognitive function.

Objective: Previous studies suggest older patients with multiple health conditions and medications may experience adverse interactions, leading to negative outcomes. However, there’s limited research on this in older adults receiving home medical care. This study assesses whether polypharmacy is linked to falls or other clinical outcomes. Methods: The study population included 217 participants, aged ≥65 years, receiving home medical care, who consented to participate in the Osaka Home Care Registry (OHCARE) study in Japan. The survey examined the association between polypharmacy and clinical outcomes. We defined “polypharmacy” as six or more medications taken regularly. Results: Of the participants, 135 (62.6%) had polypharmacy and were significantly more likely to have hypertension or diabetes. Common medications included those for hypertension, diabetes, and mental disorders. Participants with polypharmacy experienced significantly more falls. Multivariate analysis showed an association between polypharmacy and falls (odds ratio: 2.81, 95% confidence interval [1.34, 5.92]). Conclusion: Even in older patients receiving home health care, the use of six or more medications poses a risk of falls. Careful observations and life support by medical stuffs are necessary to prevent falls in older patients with polypharmacy receiving home medical care.

This study aimed to examine the associations of weight loss, low serum albumin levels, and their combination with 2-year mortality risk in older adults receiving home medical care. Participants from the Osaka Home Care Registry Study aged 65 or older were classified into two groups: low and high baseline serum albumin levels, and stratified into those with 5% weight loss and weight maintenance after 1 year. Low serum albumin and weight loss were present in 21.8% and 20.8% of participants, respectively. In multivariable Cox proportional hazards analysis, combinations involving low serum albumin were significantly associated with mortality. Participants with weight maintenance and low serum albumin (HR = 6.89, 95%CI = 2.06-23.02) and those with weight loss and low serum albumin (HR = 19.06, 95%CI = 4.42-82.14) had a higher mortality risk, whereas weight loss alone was not significant. These findings suggest that evaluating serum albumin together with weight change may help identify high-risk individuals in home medical care.