Histone modifications in embryo implantation and placentation: insights from mouse models

Embryo implantation and placentation play pivotal roles in pregnancy by facilitating crucial maternal-fetal interactions. These dynamic processes involve significant alterations in gene expression profiles within the endometrium and trophoblast lineages. Epigenetics regulatory mechanisms, such as DNA methylation, histone modification, chromatin remodeling, and microRNA expression, act as regulatory switches to modulate gene activity, and have been implicated in establishing a successful pregnancy. Exploring the alterations in these epigenetic modifications can provide valuable insights for the development of therapeutic strategies targeting complications related to pregnancy. However, our current understanding of these mechanisms during key gestational stages remains incomplete. This review focuses on recent advancements in the study of histone modifications during embryo implantation and placentation, while also highlighting future research directions in this field

Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice

One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single-cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan

Distinct TERB1 Domains Regulate Different Protein Interactions in Meiotic Telomere Movement

Summary: Meiotic telomeres attach to the nuclear envelope (NE) and drive the chromosome movement required for the pairing of homologous chromosomes. The meiosis-specific telomere proteins TERB1, TERB2, and MAJIN are required to regulate these events, but their assembly processes are largely unknown. Here, we developed a germ-cell-specific knockout mouse of the canonical telomere-binding protein TRF1 and revealed an essential role for TRF1 in directing the assembly of TERB1-TERB2-MAJIN. Further, we identified a TERB2 binding (T2B) domain in TERB1 that is dispensable for the TRF1-TERB1 interaction but is essential for the subsequent TERB1-TERB2 interaction and therefore for telomere attachment to the NE. Meanwhile, cohesin recruitment at telomeres, which is required for efficient telomere movement, is mediated by the MYB-like domain of TERB1, but not by TERB2-MAJIN. Our results reveal distinct protein interactions through various domains of TERB1, which enable the sequential assembly of the meiotic telomere complex for their movements. : During meiosis, telomeres attach to the nuclear envelope and drive the chromosome movement required for the pairing of homologous chromosomes. Zhang et al. reveal protein interaction networks within mammalian meiotic telomere complex, mediated by various domains of TERB1, which enable the sequential assembly of the complex and subsequent telomere movements. Keywords: germ cell, meiosis, telomere, chromosome, TERB1, TERB2, MAJIN, TRF1, shelteri

Association of PTGER4 and PRKAA1 genetic polymorphisms with gastric cancer

Abstract Background Gastric cancer (GC) is one of the most common malignancies, affected by several genetic loci in the clinical phenotype. This study aimed to determine the association between PTGER4 and PRKAA1 gene polymorphisms and the risk of GC. Methods A total of 509 GC patients and 507 age and sex-matched healthy controls were recruited to explore the association between PTGER4 and PRKAA1 genetic polymorphisms and GC susceptibility. Logistic regression analysis was used to study the correlation between these SNPs and GC, with odd ratio (OR) and 95% confidence interval (CI) as indicators. Multifactor dimensionality reduction was utilized to analyze the genetic relationships among SNPs. was conducted to predict gene expression, the impact of SNPs on gene expression, and the signaling pathways involved in PTGER4 and PRKAA1. Results Overall, rs10036575 in PTGER4 (OR = 0.82, p = 0.029), rs10074991 (OR = 0.82, p = 0.024) and rs13361707 (OR = 0.82, p = 0.030) in PRKAA1 were associated with susceptibility to GC. Stratification analysis revealed that the effects of these SNPs in PTGER4 and PRKAA1 on GC susceptibility were dependent on smoking and were associated with a reduced risk of adenocarcinoma (p < 0.05). Bioinformatics analysis showed an association between SNPs and corresponding gene expression (p < 0.05), and PRKAA1 may affect GC by mediating RhoA. Conclusion This study suggests that PTGER4 and PRKAA1 SNPs might affect the susceptibility of GC, providing a new biological perspective for GC risk assessment, pathogenesis exploration, and personalized treatment

PTPN13 rs989902 and CHEK2 rs738722 are associated with esophageal cancer

AbstractPurpose Individual genetic background can play an essential role in determining the development of esophageal squamous cell carcinoma (ESCC). PTPN13 and CHEK2 play important roles in the pathogenesis of ESCC. This case-control study aimed to analyze the association between gene polymorphisms and ESCC susceptibility.Methods DNA was extracted from the peripheral blood of patients. The Agena MassARRAY platform was used for the genotyping. Statistical analysis was conducted using the chi-squared test or Fisher’s exact test, logistic regression analysis, and stratification analysis.Results The ‘G’ allele of rs989902 (PTPN13) and the ‘T’ allele of rs738722 (CHEK2) were both associated with an increased risk of ESCC (rs989902: OR = 1.23, 95% CI = 1.02–1.47, p = 0.028; rs738722: OR = 1.28, 95% CI = 1.06–1.55, p = 0.011). Stratification analysis showed that SNPs (rs989902 and rs738722) were notably correlated with an increased risk of ESCC after stratification for age, sex, smoking, and drinking status. In addition, rs738722 might be associated with lower stage, while rs989902 had a lower risk of metastasis.Conclusion Our findings display that PTPN13 rs989902 and CHEK2 rs738722 are associated with an increased risk of ESCC in the Chinese Han population

Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8F/FMx1-Cre combined with a Trp53F/F mouse model that suppresses apoptosis of Chd8-/- HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation. Chd8-/-P53-/- mice exhibited severe anemia conforming to congenital dyserythropoietic anemia (CDA) phenotypes. Loss of CHD8 leads to drastically decreased numbers of orthochromatic erythroblasts and increased binucleated and multinucleated basophilic erythroblasts with a cytokinesis failure in erythroblasts. CHD8 binds directly to the gene bodies of multiple Rho GTPase signaling genes in erythroblasts, and loss of CHD8 results in their dysregulated expression, leading to decreased RhoA and increased Rac1 and Cdc42 activities. Our study shows that autism-associated CHD8 is essential for erythroblast cytokinesis

Generating Functional Multicellular Organoids from Human Placenta Villi

Abstract The interaction between trophoblasts, stroma cells, and immune cells at the maternal–fetal interface constitutes the functional units of the placenta, which is crucial for successful pregnancy outcomes. However, the investigation of this intricate interplay is restricted due to the absence of efficient experimental models. To address this challenge, a robust, reliable methodology for generating placenta villi organoids (PVOs) from early, late, or diseased pregnancies using air–liquid surface culture is developed. PVOs contain cytotrophoblasts that can self‐renew and differentiate directly, along with stromal elements that retain native immune cells. Analysis of scRNA sequencing and WES data reveals that PVOs faithfully recapitulate the cellular components and genetic alterations of the corresponding source tissue. Additionally, PVOs derived from patients with preeclampsia exhibit specific pathological features such as inflammation, antiangiogenic imbalance, and decreased syncytin expression. The PVO‐based propagation of primary placenta villi should enable a deeper investigation of placenta development and exploration of the underlying pathogenesis and therapeutics of placenta‐originated diseases