C30F12.4 influences oogenesis, fat metabolism, and lifespan in C. elegans

ABSTRACT Reproduction, fat metabolism, and longevity are intertwined regulatory axes; recent studies in C. elegans have provided evidence that these processes are directly coupled. However, the mechanisms by which they are coupled and the reproductive signals modulating fat metabolism and lifespan are poorly understood. Here, we find that an oogenesis-enriched gene, c30f12.4, is specifically expressed and located in germ cells and early embryos; when the gene is knocked out, oogenesis is disrupted and brood size is decreased. In addition to the reproductive phenotype, we find that the loss of c30f12.4 alters fat metabolism, resulting in decreased fat storage and smaller lipid droplets. Meanwhile, c30f12.4 mutant worms display a shortened lifespan. Our results highlight an important role for c30f12.4 in regulating reproduction, fat homeostasis, and aging in C. elegans, which helps us to better understand the relationship between these processes

Overexpression of human-derived DNMT3A induced intergenerational inheritance of DNA methylation and gene expression variations in rat brain and testis

In mammals, DNA methylation patterns are established by various types of DNA methyltransferases and can be stably passed on during cell division, thus creating a paradigm for epigenetic regulation that can mediate long-lasting changes in gene expression even when the initial triggering signal has disappeared. Although functional deficiency of DNMT3A, one of the methyltransferases, leads to abnormal DNA methylation patterns that result in developmental deficits in mammals, the impacts of its overexpression on tissue gene expression and DNA methylation patterns remain unclear. Here, our previously established hDNMT3A transgenic rat model and mRNA sequencing and bisulphite sequencing PCR were used to analyse the impact of hDNMT3A overexpression on tissue transcriptome and methylome, and whether the impact could be inherited intergenerationally was subsequently investigated. Our results revealed that the overexpression of hDNMT3A could induce notable gene expression variations in rat testis and brain. More importantly, 36.02% and 38.89% of these variations could be intergenerationally inherited to offspring without the transmission of the initial endogenic trigger in the brain and testis, respectively. Furthermore, we found that intergenerationally inherited DNA methylation variations in their promoters and exons could be the underlying mechanism. Compared with inheritable variations that were passively induced by environmental factors, these variations were actively induced by endogenous epigenetic modifiers. This study provided evidence for the epigenetic inheritance of endogenous factors that actively induce gene expression and DNA methylation variations; however, more studies are needed to determine the number of generations that these variations can be stably inherited

Overexpression of Human-Derived DNMT3A Induced Intergenerational Inheritance of Active DNA Methylation Changes in Rat Sperm

DNA methylation is the major focus of studies on paternal epigenetic inheritance in mammals, but most previous studies about inheritable DNA methylation changes are passively induced by environmental factors. However, it is unclear whether the active changes mediated by variations in DNA methyltransferase activity are heritable. Here, we established human-derived DNMT3A (hDNMT3A) transgenic rats to study the effect of hDNMT3A overexpression on the DNA methylation pattern of rat sperm and to investigate whether this actively altered DNA methylation status is inheritable. Our results revealed that hDNMT3A was overexpressed in the testis of transgenic rats and induced genome-wide alterations in the DNA methylation pattern of rat sperm. Among 5438 reliable loci identified with 64 primer-pair combinations using a methylation-sensitive amplification polymorphism method, 28.01% showed altered amplified band types. Among these amplicons altered loci, 68.42% showed an altered DNA methylation status in the offspring of transgenic rats compared with wild-type rats. Further analysis based on loci which had identical DNA methylation status in all three biological replicates revealed that overexpression of hDNMT3A in paternal testis induced hypermethylation in sperm of both genotype-negative and genotype-positive offspring. Among the differentially methylated loci, 34.26% occurred in both positive and negative offspring of transgenic rats, indicating intergenerational inheritance of active DNA methylation changes in the absence of hDNM3A transmission. Furthermore, 75.07% of the inheritable loci were hyper-methylated while the remaining were hypomethylated. Distribution analysis revealed that the DNA methylation variations mainly occurred in introns and intergenic regions. Functional analysis revealed that genes related to differentially methylated loci were involved in a wide range of functions. Finally, this study demonstrated that active DNA methylation changes induced by hDNMT3A expression were intergenerationally inherited by offspring without transmission of the transgene, which provided evidence for the transmission of active endogenous-factors-induced epigenetic variations