Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.

/pdf/socioeconomic-position-lifestyle-habits-and-biomarkers-of-n0u4toadu8.pdf

Socioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis.

Batesian mimicry protects animals from predators when mimics resemble distasteful models. The female-limited Batesian mimicry in Papilio butterflies is controlled by a supergene locus switching mimetic and nonmimetic forms. In Papilio polytes, recent studies revealed that a highly diversified region (HDR) containing doublesex (dsx-HDR) constitutes the supergene with dimorphic alleles and is likely maintained by a chromosomal inversion. In the closely related Papilio memnon, which exhibits a similar mimicry polymorphism, we performed whole-genome sequence analyses in 11 butterflies, which revealed a nearly identical dsx-HDR containing three genes (dsx, Nach-like, and UXT) with dimorphic sequences strictly associated with the mimetic/nonmimetic phenotypes. In addition, expression of these genes, except that of Nach-like in female hind wings, showed differences correlated with phenotype. The dimorphic dsx-HDR in P. memnon is maintained without a chromosomal inversion, suggesting that a separate mechanism causes and maintains allelic divergence in these genes. More abundant accumulation of transposable elements and repetitive sequences in the dsx-HDR than in other genomic regions may contribute to the suppression of chromosomal recombination. Gene trees for Dsx, Nach-like, and UXT indicated that mimetic alleles evolved independently in the two Papilio species. These results suggest that the genomic region involving the above three genes has repeatedly diverged so that two allelic sequences of this region function as developmental switches for mimicry polymorphism in the two Papilio species. The supergene structures revealed here suggest that independent evolutionary processes with different genetic mechanisms have led to parallel evolution of similar female-limited polymorphisms underlying Batesian mimicry in Papilio butterflies.

https://advances.sciencemag.org/content/advances/4/4/eaao5416.full.pdf

Parallel evolution of Batesian mimicry supergene in two Papilio butterflies, P. polytes and P. memnon.

The deubiquitinating enzyme ubiquitin-specific protease 3 (USP3) plays a crucial role in numerous biological processes. The aberrant expression of USP3 may have an important role in tumor development. However, the mechanism by which USP3 promotes gastric cancer (GC) metastasis remains largely unknown. Effects of USP3 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated utilizing proteomics, RT-PCR, western blotting, immunohistochemistry, immunofluorescence, cell invasion and migration assays and xenograft tumor models. USP3 expression was upregulated in GC compared with matched normal tissues and was predictive of poor survival. USP3 also promoted migration and epithelial-to-mesenchymal transition (EMT) in GC cells. Moreover, TGF-β1 induced USP3 expression, and USP3 knockdown inhibited TGF-β1-induced EMT. Furthermore, we utilized Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) to identify differentially expressed proteins in USP3-overexpressing cells compared with control cells. Importantly, we found that SUZ12 is indispensable for USP3-mediated oncogenic activity in GC. We observed that USP3 interacted with and stabilized SUZ12 via deubiquitination. SUZ12 knockdown inhibited USP3-induced migration and invasion, as well as EMT in GC cells. Examination of clinical samples confirmed that USP3 expression was positively correlated with SUZ12 protein expression and that the levels of USP3 or SUZ12 protein were negatively correlated with the levels of E-cadherin protein. These findings identify USP3 as a critical regulator. The USP3-SUZ12 axis might promote tumor progression and could be a potential therapeutic candidate for human GC.

/pdf/ubiquitin-specific-protease-3-promotes-cell-migration-and-2cg1mj70gh.pdf

Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer

In female mammals, the size of the initially established primordial follicle (PF) pool within the ovaries determines the reproductive lifespan of females. Interestingly, the establishment of the PF pool is accompanied by a remarkable programmed oocyte loss for unclear reasons. Although apoptosis and autophagy are involved in the process of oocyte loss, the underlying mechanisms require substantial study. Here, we identify a new role of lysine-specific demethylase 1 (LSD1) in controlling the fate of oocytes in perinatal mice through regulating the level of autophagy. Our results show that the relatively higher level of LSD1 in fetal ovaries sharply reduces from 18.5 postcoitus (dpc). Meanwhile, the level of autophagy increases while oocytes are initiating programmed death. Specific disruption of LSD1 resulted in significantly increased autophagy and obviously decreased oocyte number compared with the control. Conversely, the oocyte number is remarkably increased by the overexpression of Lsd1 in ovaries. We further demonstrated that LSD1 exerts its role by regulating the transcription of p62 and affecting autophagy level through its H3K4me2 demethylase activity. Finally, in physiological conditions, a decrease in LSD1 level leads to an increased level of autophagy in the oocyte when a large number of oocytes are being lost. Collectively, LSD1 may be one of indispensible epigenetic molecules who protects oocytes against preterm death through repressing the autophagy level in a time-specific manner. And epigenetic modulation contributes to programmed oocyte death by regulating autophagy in mice.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/acel.13102

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62.

Studies over the past decades have elucidated the critical role of autophagy in human health and diseases. Although the processes of autophagy in the cytoplasm have been well studied, the posttranscriptional and epigenetic regulation mechanisms of autophagy are still poorly understood. Protein methylation, including histone methylation and non-histone protein methylation, is the most important type of posttranscriptional and epigenetic modification. Recent studies have shown that protein methylation is associated with effects on autophagosome formation, autophagy-related protein expression, and signaling pathway activation, but the details are still unclear. Thus, it is important to summarize the current status and discuss the future directions of research on protein methylation in the context of autophagy.

Protein methylation functions as the posttranslational modification switch to regulate autophagy.

Unlike other members of the polycomb group protein family, EZH1 has been shown to positively associate with active transcription on a genome-wide scale. However, the underlying mechanism for this behavior still remains elusive. Here, we report that EZH1 physically interacts with UXT, a small chaperon-like transcription co-activator. UXT specifically interacts with EZH1 and SUZ12, but not EED. Similar to upon knockdown of UXT, knockdown of EZH1 or SUZ12 through RNA interference in the cell impairs the transcriptional activation of nuclear factor (NF)-κB target genes induced by TNFα. EZH1 deficiency also increases TNFα-induced cell death. Interestingly, chromatin immunoprecipitation and the following next-generation sequencing analysis show that H3K27 mono-, di- and tri-methylation on NF-κB target genes are not affected in EZH1- or UXT-deficient cells. EZH1 also does not affect the translocation of the p65 subunit of NF-κB (also known as RELA) from the cytosol to the nucleus. Instead, EZH1 and SUZ12 regulate the recruitment of p65 and RNA Pol II to target genes. Taken together, our study shows that EZH1 and SUZ12 act as positive regulators for NF-κB signaling and demonstrates that EZH1, SUZ12 and UXT work synergistically to regulate pathway activation in the nucleus.

The EZH1-SUZ12 complex positively regulates the transcription of NF-κB target genes through interaction with UXT.

Inhibition of H3K4 demethylation induces autophagy in cancer cell lines

ILF3 represses repeat-derived microRNAs targeting RIG-I mediated type I interferon response.

Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development. 

/pdf/regulation-of-kdm5c-stability-and-enhancer-reprogramming-in-1daqq9zl.pdf

Regulation of KDM5C stability and enhancer reprogramming in breast cancer

In eukaryote cells, core components of chromatin, such as histones and DNA, are packaged in nucleus. Leakage of nuclear materials into cytosol will induce pathological effects. However, the underlying mechanisms remain elusive. Here, cytoplasmic localization of nuclear materials induced by chromatin dysregulation (CLIC) in mammalian cells is reported. H3K9me3 inhibition by small chemicals, HP1α knockdown, or knockout of H3K9 methylase SETDB1, induces formation of cytoplasmic puncta containing histones H3.1, H4 and cytosolic DNA, which in turn activates inflammatory genes and autophagic degradation. Autophagy deficiency rescues H3 degradation, and enhances the activation of inflammatory genes. MRE11, a subunit of MRN complex, enters cytoplasm after heterochromatin dysregulation. Deficiency of MRE11 or NBS1, but not RAD50, inhibits CLIC puncta in cytosol. MRE11 depletion represses tumor growth enhanced by HP1α deficiency, suggesting a connection between CLIC and tumorigenesis. This study reveals a novel pathway that heterochromatin dysregulation induces translocation of nuclear materials into cytoplasm, which is important for inflammatory diseases and cancer.

Epigenetic Dysregulation Induces Translocation of Histone H3 into Cytoplasm.

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