Transcription of endogenous retroviruses (ERVs) is inhibited by de novo DNA methylation during gametogenesis, a process initiated after birth in oocytes and at approximately embryonic day 15.5 (E15.5) in prospermatogonia. Earlier in germline development, the genome, including most retrotransposons, is progressively demethylated. Young ERVK and ERV1 elements, however, retain intermediate methylation levels. As DNA methylation reaches a low point in E13.5 primordial germ cells (PGCs) of both sexes, we determined whether retrotransposons are marked by H3K9me3 and H3K27me3 using a recently developed low-input ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) method. Although these repressive histone modifications are found predominantly on distinct genomic regions in E13.5 PGCs, they concurrently mark partially methylated long terminal repeats (LTRs) and LINE1 elements. Germline-specific conditional knockout of the H3K9 methyltransferase SETDB1 yields a decrease of both marks and DNA methylation at H3K9me3-enriched retrotransposon families. Strikingly, Setdb1 knockout E13.5 PGCs show concomitant derepression of many marked ERVs, including intracisternal A particle (IAP), ETn, and ERVK10C elements, and ERV-proximal genes, a subset in a sex-dependent manner. Furthermore, Setdb1 deficiency is associated with a reduced number of male E13.5 PGCs and postnatal hypogonadism in both sexes. Taken together, these observations reveal that SETDB1 is an essential guardian against proviral expression prior to the onset of de novo DNA methylation in the germline.

/pdf/setdb1-is-required-for-germline-development-and-silencing-of-46hk19inc1.pdf

Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

The intricate molecular and cellular interactions between spermatogonial stem cells (SSCs) and their cognate niche form the basis for life-long sperm production. To maintain long-term fertility and sustain sufficiently high levels of spermatogenesis, a delicate balance needs to prevail between the different niche factors that control cell fate decisions of SSCs by promoting self-renewal, differentiation priming or spermatogenic commitment of undifferentiated spermatogonia (Aundiff). Previously the SSC niche was thought to be formed primarily by Sertoli cells. However, recent research has indicated that many distinct cell types within the testis contribute to the SSC niche including most somatic cell populations and differentiating germ cells. Moreover, postnatal testis development involves maturation of somatic supporting cell populations and onset of cyclic function of the seminiferous epithelium. The stochastic and flexible behavior of Aundiff further complicates the definition of the SSC niche. Unlike in invertebrate species, providing a simple anatomical description of the SSC niche in the mouse is therefore challenging. Rather, the niche needs to be understood as a dynamic system that is able to serve the long-term reproductive function and maintenance of fertility both under steady-state and during development plus regeneration. Recent data from us and others have also shown that Aundiff reversibly transition between differentiation-primed and self-renewing states based on availability of niche-derived cues. This review focuses on defining the current understanding of the SSC niche and the elements involved in its regulation.

/pdf/molecular-regulation-of-spermatogonial-stem-cell-renewal-and-2qstwl6g2k.pdf

Molecular regulation of spermatogonial stem cell renewal and differentiation.

Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation dominant) vs. more differentiated cells (DNA methylation dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, on loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency.

https://www.pnas.org/content/pnas/112/27/8367.full.pdf

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

SETDB1 (SET domain bifurcated histone lysine methyltransferase 1) is a protein lysine methyltransferase and methylates histone H3 at lysine 9 (H3K9). Among other H3K9 methyltransferases, SETDB1 and SETDB1-mediated H3K9 trimethylation (H3K9me3) play pivotal roles for silencing of endogenous and exogenous retroelements, thus contributing to genome stability against retroelement transposition. Furthermore, SETDB1 is highly upregulated in various tumor cells. In this article, we describe recent advances about how SETDB1 activity is regulated, how SETDB1 represses various types of retroelements such as L1 and class I, II, and III endogenous retroviruses (ERVs) in concert with other epigenetic factors such as KAP1 and the HUSH complex and how SETDB1-mediated H3K9 methylation can be maintained during replication.

https://www.mdpi.com/1999-4915/12/6/596/pdf

SETDB1-Mediated Silencing of Retroelements.

BACKGROUND Subfertility affects approximately 15% of all couples, and a severe male factor is identified in 17% of these couples. While the etiology of a severe male factor remains largely unknown, prior gonadotoxic treatment and genomic aberrations have been associated with this type of subfertility. Couples with a severe male factor can resort to ICSI, with either ejaculated spermatozoa (in case of oligozoospermia) or surgically retrieved testicular spermatozoa (in case of azoospermia) to generate their own biological children. Currently there is no direct treatment for azoospermia or oligozoospermia. Spermatogonial stem cell (SSC) autotransplantation (SSCT) is a promising novel clinical application currently under development to restore fertility in sterile childhood cancer survivors. Meanwhile, recent advances in genomic editing, especially the clustered regulatory interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) system, are likely to enable genomic rectification of human SSCs in the near future. OBJECTIVE AND RATIONALE The objective of this review is to provide insights into the prospects of the potential clinical application of SSCT with or without genomic editing to cure spermatogenic failure and to prevent transmission of genetic diseases. SEARCH METHODS We performed a narrative review using the literature available on PubMed not restricted to any publishing year on topics of subfertility, fertility treatments, (molecular regulation of) spermatogenesis and SSCT, inherited (genetic) disorders, prenatal screening methods, genomic editing and germline editing. For germline editing, we focussed on the novel CRISPR-Cas9 system. We included papers written in English only. OUTCOMES Current techniques allow propagation of human SSCs in vitro, which is indispensable to successful transplantation. This technique is currently being developed in a preclinical setting for childhood cancer survivors who have stored a testis biopsy prior to cancer treatment. Similarly, SSCT could be used to restore fertility in sterile adult cancer survivors. In vitro propagation of SSCs might also be employed to enhance spermatogenesis in oligozoospermic men and in azoospermic men who still have functional SSCs albeit in insufficient numbers. The combination of SSCT with genomic editing techniques could potentially rectify defects in spermatogenesis caused by genomic mutations or, more broadly, prevent transmission of genomic diseases to the offspring. In spite of the promising prospects, SSCT and germline genomic editing are not yet clinically applicable and both techniques require optimization at various levels. WIDER IMPLICATIONS SSCT with or without genomic editing could potentially be used to restore fertility in cancer survivors to treat couples with a severe male factor and to prevent the paternal transmission of diseases. This will potentially allow these couples to have their own biological children. Technical development is progressing rapidly, and ethical reflection and societal debate on the use of SSCT with or without genomic editing is pressing.

/pdf/spermatogonial-stem-cell-autotransplantation-and-germline-3g57zlomgx.pdf

Spermatogonial stem cell autotransplantation and germline genomic editing: a future cure for spermatogenic failure and prevention of transmission of genomic diseases

Purpose: This systematic review and meta-analysis aims to investigate the cognitive benefits of breaking up prolonged sitting (PS) by acute physical exercises (PE). Methods: A systematic literature search was performed in six electronic databases (PubMed, Scopus, Web of Science, PsycINFO, SPORTDiscus, and Cochrane Library) to identify cross-over studies with a pre-posttest design that examined the effects of PE breaks during 3 to 5 h of prolonged sitting on cognitive performance. A meta-analysis was performed using a random effects model, with subgroup analyses investigating dose-response effects and differences between cognitive domains. Additionally, study quality was rated using the PEDro scale. Results: Thirteen randomized controlled trials (RCTs) with a total of 295 participants (171 female and 124 male) were included in this systematic review. Thereof, nine studies were included in our meta-analysis. We observed that during PS, PE breaks did not improve overall cognitive performance (Hedges g=-0.043[-0.158,0.073]). There was no between-study heterogeneity indicated. This is further supported by the subgroup analyses showing no differences in effect sizes between cognitive domains and different exercise intensities. Conclusions: Our findings suggest that interrupting PS by PE breaks neither improved, nor impaired cognitive performance. Consequently, PE breaks during PS allows to integrate regular physical activity in daily routines (i.e., through PE breaks) without compromising the performance of cognitively demanding tasks. Keywords: Prolonged sitting; physical activity; exercise; cognition; meta-analysis

The Acute Effects of Physical Exercise Breaks on Cognitive Function During Prolonged Sitting: A First Quantitative Evidence

CO78 Efficacy and Safety of Brigatinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Systematic Review and Meta-Analysis

Objective To explore the relationship between blood pressure and the risk of acute myocardial infarction (AMI) in Chinese adults. Methods This prospective cohort study included 26,794 participants which were recruited from 60 surveillance sites in 2010 China Chronic Disease Risk Factor Surveillance and followed-up survey was conducted from 2016 to 2017. Data were collected by questionnaires, physical measurements and laboratory tests. Blood pressure was grouped by systolic blood pressure and diastolic blood pressure, and cox proportional hazards regression models were used to analyze the relationship between blood pressure and risk of AMI. Results A total of 256 AMI events occurred among 160,386.38 person-years follow-up and the incidence of AMI was 159.6/100,000 person-years. After adjusting for age, sex, income, education, marital status, physical activity, drinking, abdominal obesity, BMI, dyslipidemia and diabetes, compared with normotension group, the risk of AMI onset was increased by 61% (HR=1.61, 95% CI: 1.17?2.21), 60% (HR=1.60, 95% CI: 1.17?2.20), 84% (HR=1.84, 95% CI: 1.26?2.68) and 120% (HR=2.20, 95% CI: 1.43?3.38) in systolic diastolic hypertension(SDH), hypertension grade 1(mild), hypertension grade 2(moderate), hypertension grade 3(severe), respectively. In addition, after adjusting for relevant factors, the relationship between hypertension and the risk of AMI may be influenced by abdominal obesity, diabetes and lack of physical activity. Conclusions The incidence of AMI appears to be considerable among Chinese adults and hypertension is an independent risk factor for its onset. The risk of AMI is higher in participants with more severe hypertension.

/pdf/relationship-between-blood-pressure-and-the-risk-of-acute-1w3uo2vz.pdf

Relationship between blood pressure and the risk of acute myocardial infarction in Chinese adults: a prospective study

Self-renewal and differentiation of spermatogonial stem cells (SSCs) are the foundation of spermatogenesis throughout a male's life. SSC transplantation will be a valuable solution for young male patients to preserve their fertility. As SSCs in the collected testis tissue from the patients are very limited, it is necessary to expansion the SSCs in vitro. Previous studies suggested that histone methyltransferase ERG-associated protein with SET domain (ESET) represses gene expression and is essential for the maintenance of the pool of embryonic stem cells and neurons. The objective of this study was to determine the role of ESET in SSCs using in vitrocell culture and germ cell transplantation. Cell transplantation assay showed that knockdown of ESET reduced the number of seminiferous tubules with spermatogenesis when compared with that of the control. Knockdown of ESET also upregulated the expression of apoptosis-associated genes (such as P53, Caspase9, Apaf1), whereas inhibited the expression of apoptosis-suppressing genes (such as Bcl2l1, X-linked inhibitor of apoptosis protein). In addition, suppression of ESET led to increase in expression of Caspase9 and activation of Caspase3 (P17) as well as cleavage of poly (ADP-ribose) polymerase. Among the five ESET-targeting genes (Cox4i2, spermatogenesis and oogenesis Specific Basic Helix-Loop-Helix 2, Nobox, Foxn1 and Dazl) examined by ChIP assay, Cox4i2 was found to regulate SSC apoptosis by the rescue experiment. BSP analyses further showed that DNA methylation in the promoter loci of Cox4i2was influenced by ESET, indicating that ESET also regulated gene expression through DNA methylation in addition to histone methylation. In conclusion, we found that ESET regulated SSC apoptosis by suppressing of Cox4i2 expression through histone H3 lysine 9 tri-methylation and DNA methylation. The results obtained will provide unique insights that would broaden the research on SSC biology and contribute to the treatment of male infertility.

/pdf/the-histone-methyltransferase-eset-is-required-for-the-2wwejqyyfi.pdf

The histone methyltransferase ESET is required for the survival of spermatogonial stem/progenitor cells in mice

Background: T cell malignancies represent a group of hematologic cancers with high relapse and mortality rates. The shared expression of target antigens between chimeric antigen receptor (CAR) T cells and malignant T cells has limited the development of CAR-T due to unintended CAR-T fratricide. Here, we develop a fratricide-resistant anti-CD7 CAR-T modified by CD7 ablation through CRISPR/CAS9 gene editing (KO7CAR). Aims: In a phase I clinical trial, we explored the efficacy and safety of KO7CAR T-cells for relapsed or refractory (R/R) T-cell malignancies (NCT04916860 & NCT04938115). Methods: Peripheral blood mononuclear cells were collected from patients (n=13) or the transplant donor (n=2) by leukapheresis. CD7-ablated CAR T cells (KO7CAR) were derived by electroporation of bulk T cells with CD7-targeting Cas9-gRNA RNP 24 hours before 7CAR transduction. This KO7CAR is a second-generation CAR-T with the co-stimulatory domain of 4-1BB and CD3ζ targeting CD7. Intravenous fludarabine (30mg/m2/d) and cyclophosphamide (300mg/m2/d) were given to all patients on day -5 to day -3 prior to KO7CAR-T cells infusion. Results: From Oct. 2020 to Oct. 2021, 15 patients with T-cell acute lymphoblastic leukemia (n=10), T-cell lymphoblastic lymphoma (n=3), and mixed phenotype acute leukemia (n=2) were enrolled and received KO7 CAR-T cells (Table 1). The median age was 28 (8-46) years old. Four patients had prior hematopoietic stem cell transplantation (HSCT). At enrollment, 10 patients had bone marrow (BM) blasts >5% by morphology, and 10 patients had the extramedullary disease (EMD, diffuse involvement, n=8, and bulky mediastinal masses, n=2). Both patient- and donor-derived KO7CAR-T cells were successfully generated with a transduction efficiency of 59.0% (22.5%-97.4%). A single dose of KO7CAR-T cells was infused to patients at low dose (1.5~5x105 cells/kg, n=8), medium dose (1x106 cells/kg, n=6) or high dose (2x106 cells/kg, n=1). On day 28, 15/15 (100%) patients achieved minimal residual disease (MRD) negative complete remission (CR). Among the 10 patients with EMD, 7 achieved EMD CR on day 30, 2 achieved partial response (PR), and 1 who relapsed post 2nd transplant had no response on day 35 then withdrew. Up to data cutoff Feb.10, 2022, the median follow-up time was of 309 days (35~407 days). About 2 months post KO7CAR, 12 patients bridged into allogeneic HSCT, and all remained progression-free after a median time of 253 (30~388) days after HSCT except for 1 who relapsed on day 147 then died from intracerebral hemorrhage on day 249. The other 2 patients without subsequent HSCT (all had a prior transplant) died from infection on day 78 and GVHD on day 103, respectively, post KO7CAR. Mild cytokine release syndrome (CRS, ≤grade II) occurred in 10/15 (66.7%) patients, and 5/15(33.3%) patients had grade III CRS. One patient had grade I neurotoxicity, and 2 had grade III/IV neurotoxicity. All was controlled after the administration of corticosteroids and/or tocilizumab. Following infusion, the median peak of circulating KO7CAR-T cells was 1.77×105 (0.279~14.3×105) copies/μg genomic DNA which occurred around day 20 (day10~ day25) and 63.47% (23.1%~94.18%) occurring on day15 (day 9~day25) by q-PCR and flow cytometry respectively. Image:Summary/Conclusion: This study demonstrated KO7CAR-T therapy had a high efficacy for CD7+ T-cell malignancies even for those who relapsed post-transplant. Safety was manageable, however, more data on additional patients and longer observation time are needed to evaluate the efficacy of KO7 CAR-T products further. 

S110: a novel and successful cd7 gene knockout car-t cell therapy for relapsed or refractory t-cell hematologic malignancies

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