Asymmetric cell divisions (ACDs) generate two daughter cells with identical genetic information but distinct cell fates through epigenetic mechanisms. However, the process of partitioning different epigenetic information into daughter cells remains unclear. Here, we demonstrate that the nucleosome remodeling and deacetylase (NuRD) complex is asymmetrically segregated into the surviving daughter cell rather than the apoptotic one during ACDs in Caenorhabditis elegans. The absence of NuRD triggers apoptosis via the EGL-1-CED-9-CED-4-CED-3 pathway, while an ectopic gain of NuRD enables apoptotic daughter cells to survive. We identify the vacuolar H+-adenosine triphosphatase (V-ATPase) complex as a crucial regulator of NuRD\'s asymmetric segregation. V-ATPase interacts with NuRD and is asymmetrically segregated into the surviving daughter cell. Inhibition of V-ATPase disrupts cytosolic pH asymmetry and NuRD asymmetry. We suggest that asymmetric segregation of V-ATPase may cause distinct acidification levels in the two daughter cells, enabling asymmetric epigenetic inheritance that specifies their respective life-versus-death fates.

Circular RNA (circRNA) has emerged as potential therapeutic targets for cardiovascular diseases. Given the central role of the TGFβ signaling pathway in cardiac remodeling and its potential as a therapeutic target, we hypothesized that a circRNA from this pathway could modulate cardiac remodeling and serve as a heart failure treatment. Therefore, we identified a circRNA, named circSMAD3, that was significantly reduced in murine heart failure models. Functionally, circSMAD3 mitigated cardiomyocyte hypertrophy and inhibited cardiac fibroblast activation in vitro. Mechanistically, circSMAD3 interacts with YBX1, stabilizing it and facilitating its binding to SMAD3 in the nucleus, disrupting the TGFβ/SMAD3 signaling pathway, and ultimately restoring cardiac remodeling. This study highlights circSMAD3 as a promising therapeutic target for heart failure treatment.

Bromodomain protein BRD4 binds to acetylated histones to regulate transcription. BRD4 also drives cancer cell proliferation. However, the role of BRD4 in normal cell growth has remained unclear. Here, we investigated this question by using mouse embryonic fibroblasts with conditional Brd4 knockout (KO). We found that Brd4KO cells grow more slowly than wild type cells; they do not complete replication, fail to achieve mitosis, and exhibit extensive DNA damage throughout all cell cycle stages. BRD4 was required for expression of more than 450 cell cycle genes including genes encoding core histones and centromere/kinetochore proteins that are critical for genome replication and chromosomal segregation. Moreover, we show that many genes controlling R-loop formation and DNA damage response (DDR) require BRD4 for expression. Finally, BRD4 constitutively occupied genes controlling R-loop, DDR and cell cycle progression. In summary, BRD4 epigenetically marks above genes and serves as a master regulator of normal cell growth.

PARP inhibitors (PARPi) are efficacious in BRCA1-null tumors; however, their utility is limited in tumors with functional BRCA1. We hypothesized that pharmacologically reducing BRCA1 protein levels could enhance PARPi effectiveness in BRCA1 wild-type tumors. To identify BRCA1 downregulating agents, we generated reporter cell lines using CRISPR-mediated editing to tag endogenous BRCA1 protein with HiBiT. These reporter lines enable the sensitive measurement of BRCA1 protein levels by luminescence. Validated reporter cells were used in a pilot screen of epigenetic-modifying probes and a larger screen of more than 6,000 compounds. We identified 7 compounds that could downregulate BRCA1-HiBiT expression and synergize with olaparib. Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.

Sucrose is the transport form of carbohydrate in plants serving as signal molecule besides nutrition, but the signaling is elusive. Here, neutral invertase 8 (OsNIN8) mutated at G461R into OsNIN8m, which increased its charge and hydrophobicity, decreased hydrolysis of sucrose to 13% and firmer binding to sucrose than the wildtype. This caused downstream metabolites and energy accumulation forming overnutrition. Paradoxically, division of subinitials in longitudinal cell lineages was only about 15 times but more than 100 times in wildtype, resulting in short radicle. Further, mutation of OsNIN8 into deficiency of hydrolysis but maintenance of sucrose binding allowed cell division until ran out of energy showing the association but not hydrolysis gave the signal. Chemically, sucrose binding to OsNIN8 was exothermic but to OsNIN8m was endothermic. Therefore, OsNIN8m lost the signal function owing to change of thermodynamic state. So, OsNIN8 sensed sucrose for cell division besides hydrolyzed sucrose.

Although up to 80% small cell lung cancer (SCLC) patients\' response is good for first-line chemotherapy regimen, most patients develop recurrence of the disease within weeks to months. Here, we report cytostatic effect of leflunomide (Leflu) and teriflunomide (Teri) on SCLC cell proliferation through inhibition of DRP1 phosphorylation at Ser616 and decreased mitochondrial fragmentation. When administered together, Teri and carboplatin (Carbo) act synergistically to significantly inhibit cell proliferation and DRP1 phosphorylation, reduce abundance of intermediates in pyrimidine de novo pathway, and increase apoptosis and DNA damage. Combination of Leflu&Carbo has anti-tumorigenic effect in vivo. Additionally, lurbinectedin (Lur) and Teri potently and synergistically inhibited spheroid growth and depleted uridine and DRP1 phosphorylation in mouse tumors. Our results suggest combinations of Carbo and Lur with Teri or Leflu are efficacious and underscore how the relationship between DRP1/DHODH and mitochondrial plasticity serves as a potential therapeutic target to validate these treatment strategies in SCLC clinical trials.

Retinoic acid (RA), derived from retinol (ROL), is integral to cell growth, differentiation, and organogenesis. It is known that RA can inhibit herpes simplex virus (HSV) replication, but the interactions between alphaherpesviruses and RA metabolism are unclear. Our present study revealed that alphaherpesvirus (HSV-1 and Pseudorabies virus, PRV) infections suppressed RA synthesis from ROL by activating P53, which increased retinol reductase 3 (DHRS3) expression-an enzyme that converts retinaldehyde back to ROL. This process depended on the virus-triggered DNA damage response, the degradation of class I histone deacetylases, and the subsequent hyperacetylation of histones H3 and H4. Counteracting DHRS3 or P53 enabled higher RA synthesis and reduced viral growth. RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections.

Fibroblastic reticular cells (FRCs) are mesenchymal stromal cells in human lymph nodes (LNs) playing a pivotal role in adaptive immunity. Several FRC subsets have been identified, yet it remains to be elucidated if their heterogeneity is maintained upon culture. Here, we established a protocol to preserve and culture FRCs from human LNs and characterized their phenotypic profile in fresh LN suspensions and upon culture using multispectral flow cytometry. We found nine FRC subsets in fresh human LNs, independent of donor, of which four persisted in culture throughout several passages. Interestingly, the historically FRC-defining marker podoplanin (PDPN) was not present on all FRC subsets. Therefore, we propose that CD45negCD31neg human FRCs are not restricted by PDPN expression, as we found CD90, BST1, and CD146/MCAM to be more widely expressed. Together, our data provide insight into FRC heterogeneity in human LNs, enabling further investigation into the function of individual FRC subsets.

Point mutations in KIF22 have been linked to spondyloepimetaphyseal dysplasia with joint laxity, type 2 (SEMDJL2). Skeletal features of SEMDJL2 include short stature and joint laxity. Mechanisms underlying these limb abnormalities are unknown. Here in this manuscript, we have investigated the function of KIF22 in chondrocytes. Quantitative PCR and immunostaining revealed that Kif22 was highly expressed in proliferating-zone growth-plate chondrocytes. Kif22 knockdown resulted in defective mitotic spindle formation and reduced cell proliferation. Forced expression of SEMDJL-associated mutant Kif22 constructs likewise induced abnormal mitotic spindle morphology and reduced proliferation. Mice expressing a KIF22 truncation mutant had shorter growth plates and shorter tibial bones compared to wild-type mice. These results suggest that KIF22 regulates mitotic spindle formation in proliferating chondrocytes thereby linking the stunted longitudinal bone growth observed in SEMDJL2 to failures of chondrocyte division.

Diagnosis of tuberculosis remains a challenge when microbiological tests are negative. Immune cell atlas of patients with tuberculosis and healthy controls were established by single-cell transcriptome. Through integrated analysis of scRNA-seq with microarray and bulk RNA sequencing data, a ferroptosis-related gene signature containing ACSL4, CTSB, and TLR4 genes that were associated with tuberculosis disease was identified. Four gene expression datasets from blood samples of patients with tuberculosis, latent tuberculosis infection, and healthy controls were used to assess the diagnostic value of the gene signature. The areas under the ROC curve for the combined gene signature were 1.000, 0.866, 0.912, and 0.786, respectively, in differentiating active tuberculosis from latent infection. During anti-tuberculosis treatment, the expression of the gene signature decreased significantly in cured patients with tuberculosis. In conclusion, the ferroptosis-related gene signature was associated with tuberculosis treatment efficacy and was a promising biomarker for differentiating active tuberculosis from latent infection.