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The UHRF protein family consists of multidomain regulatory proteins that sense modification status of DNA and/or proteins and catalyze the ubiquitylation of target proteins. Through their functional domains, they interact with other molecules and serve as a hub for regulatory networks of several important biological processes, including maintenance of DNA methylation and DNA damage repair. The UHRF family is conserved in vertebrates and plants but is missing from fungi and many nonvertebrate animals. Mammals commonly have UHRF1 and UHRF2, but, despite their high structural similarity, the two paralogues appear to have distinct functions. Furthermore, UHRF1 and UHRF2 show different expression patterns and different outcomes in gene knockout experiments. In this review, we summarize the current knowledge on the molecular function of the UHRF family in various biological pathways and discuss their roles in epigenetics, development, gametogenesis, and carcinogenesis, with a focus on the mammalian UHRF proteins.

This study investigates the yield-seeking behavior of income-oriented institutional investors, who are essential players in financial markets. While external pressures compelling firms to “reach for yield” are well-documented, the firm-level behavioral drivers underlying this phenomenon remain largely underexplored. Drawing on the behavioral theory of the firm, this study argues that an investor’s performance relative to their social aspiration level (the peer average) influences their yield-seeking decisions, and that this effect is moderated by “portfolio slack,” defined as unrealized gains or losses. To test this theory in the context of persistent low-yield pressure, this study constructs and analyzes a panel dataset of Japanese life insurance companies from 2000 to 2019. The analysis reveals that these investors increase their portfolio income yield after underperforming their peers and decrease it after outperforming. Furthermore, greater portfolio slack amplifies yield increases after underperformance and mitigates yield decreases after outperformance. In contrast, organizational slack primarily mitigates yield reductions after outperformance. This research extends the behavioral theory of the firm to the asset management context by identifying distinct performance feedback responses and proposing portfolio slack as an important analytical construct, thereby offering key insights for investment managers and financial regulators.

The behavioral theory of the firm explains how firms react to performance feedback, yet little is known about how firms integrate backward-looking feedback with forward-looking assessments of market opportunity. This study proposes and tests a retrenchment model grounded in SWOT-based behavioral logic via the TOWS matrix. Changes in market share are conceptualized as an internal strength or weakness, and market attractiveness, as an external opportunity or threat. Using prefecture-level panel data on Japanese life insurance companies (2006-2019), the analysis showed that market attractiveness served as a cognitive frame that shapes a firm's response to performance signals. In attractive markets (opportunity), firms reduced retrenchment, as share gains (strength) were leveraged and losses (weakness) triggered problem-solving. Conversely, in unattractive markets (threat), firms accelerated retrenchment, as losses (weakness) confirmed the need to exit and gains (strength) enabled a profitable withdrawal. The study extends behavioral theory by showing that the strategic meaning of an internal strength or weakness depends on the external context of an opportunity or threat. This mechanism helps explain why firms sometimes persist after failure and retrench after success. Practically, the findings offer a diagnostic framework that helps managers assess market portfolios and mitigate behavioral biases in resource allocation decisions.

Key Points Accumulating evidence indicates that epigenetic modifiers have key roles in genome-wide reprogramming and activation and repression of specific genes during mammalian germ-cell development. Germ-cell specification and suppression of the somatic gene expression programme might involve epigenetic modifications. Furthermore, differentiating primordial germ cells (PGCs) show global reduction in repressive epigenetic marks, and activation and repression of post-migratory PGC-specific genes involves DNA methylation and histone-arginine methylation. In post-migratory PGCs, epigenetic imprints that are specific to the parent of origin are erased. Subsequently, sex-specific imprints are established during male and female gametogenesis, and the de novo DNA methylation machinery has a central role in this process. DNA methylation is important for silencing retrotransposons in germ cells and therefore contributes to the maintenance of genomic integrity. Recent studies have revealed a link between DNA methylation and small-RNA-mediated silencing mechanisms. A number of histone methyltransferases are essential for establishing a chromosome structure that is appropriate for events that occur during meiosis and for activation and repression of genes that are necessary or unnecessary for meiosis. Meiotic sex-chromosome inactivation in male germ cells involves histone variants and epigenetic modifications. Global nuclear remodelling including histone–protamine exchange occurs in haploid spermatids. Expression of some haploid-specific genes relies on histone demethylation. A better understanding of the epigenetic regulation of germ-cell development will be of great importance for improvement of reproductive engineering technologies and human health. The epigenetic profile of germ cells undergoes several significant changes that are essential for post-fertilization development to occur. An emerging theme from recent studies is that epigenetic modifiers also have key roles in the development of germ cells themselves. The epigenetic profile of germ cells, which is defined by modifications of DNA and chromatin, changes dynamically during their development. Many of the changes are associated with the acquisition of the capacity to support post-fertilization development. Our knowledge of this aspect has greatly increased— for example, insights into how the re-establishment of parental imprints is regulated. In addition, an emerging theme from recent studies is that epigenetic modifiers have key roles in germ-cell development itself — for example, epigenetics contributes to the gene-expression programme that is required for germ-cell development, regulation of meiosis and genomic integrity. Understanding epigenetic regulation in germ cells has implications for reproductive engineering technologies and human health.

Human pluripotent stem cells (hPSCs) have been induced into human primordial germ cell–like cells (hPGCLCs) in vitro, the first step toward human in vitro gametogenesis. Yamashiro et al. went a step closer to generating mature gametes by culturing hPSCs with mouse embryonic ovarian somatic cells in xenogeneic reconstituted ovaries (see the Perspective by Gill and Peters). Over a period of 4 months, hPGCLCs underwent hallmark epigenetic reprogramming and differentiated progressively into cells closely resembling human oogonia, an immediate embryonic precursor for human oocytes. This study creates opportunities for human germ cell research and provides a foundation for human in vitro gametogenesis. Science , this issue p. 356 ; see also p. 291 Human primordial germ cell–like cells differentiate into oogonia in xenogeneic reconstituted ovaries in vitro. Human in vitro gametogenesis may transform reproductive medicine. Human pluripotent stem cells (hPSCs) have been induced into primordial germ cell–like cells (hPGCLCs); however, further differentiation to a mature germ cell has not been achieved. Here, we show that hPGCLCs differentiate progressively into oogonia-like cells during a long-term in vitro culture (approximately 4 months) in xenogeneic reconstituted ovaries with mouse embryonic ovarian somatic cells. The hPGCLC-derived oogonia display hallmarks of epigenetic reprogramming—genome-wide DNA demethylation, imprint erasure, and extinguishment of aberrant DNA methylation in hPSCs—and acquire an immediate precursory state for meiotic recombination. Furthermore, the inactive X chromosome shows a progressive demethylation and reactivation, albeit partially. These findings establish the germline competence of hPSCs and provide a critical step toward human in vitro gametogenesis.

Epigenetic reprogramming of the zygote involves dynamic incorporation of histone variant H3.3. However, the genome-wide distribution and dynamics of H3.3 during early development remain unknown. Here, we delineate the H3.3 landscapes in mouse oocytes and early embryos. We unexpectedly identify a non-canonical H3.3 pattern in mature oocytes and zygotes, in which local enrichment of H3.3 at active chromatin is suppressed and H3.3 is relatively evenly distributed across the genome. Interestingly, although the non-canonical H3.3 pattern forms gradually during oogenesis, it quickly switches to a canonical pattern at the two-cell stage in a transcription-independent and replication-dependent manner. We find that incorporation of H3.1/H3.2 mediated by chromatin assembly factor CAF-1 is a key process for the de novo establishment of the canonical pattern. Our data suggest that the presence of the non-canonical pattern and its timely transition toward a canonical pattern support the developmental program of early embryos. Ultra-low-input native ChIP-seq analyses of genome-wide histone H3.3 distribution during early mouse development reveal a CAF-1-dependent transition from a non-canonical pattern in the oocyte and zygote to a canonical distribution at the two-cell stage.

Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and an SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome types 3 and 4. Here, we demonstrate that the classical nonhomologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS, coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7- and HELLS-deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of γH2AX signals. Although less prominent, cells with mutations in the other ICF genes DNMT3B and ZBTB24 (responsible for ICF types 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis.

Microbiota-derived short-chain fatty acids (SCFAs) and organic acids produced by the fermentation of non-digestible fibre can communicate from the microbiome to host tissues and modulate homeostasis in mammals. The microbiome has circadian rhythmicity and helps the host circadian clock function. We investigated the effect of SCFA or fibre-containing diets on circadian clock phase adjustment in mouse peripheral tissues (liver, kidney, and submandibular gland). Initially, caecal SCFA concentrations, particularly acetate and butyrate, induced significant day-night differences at high concentrations during the active period, which were correlated with lower caecal pH. By monitoring luciferase activity correlated with the clock gene Period2 in vivo , we found that oral administration of mixed SCFA (acetate, butyrate, and propionate) and an organic acid (lactate), or single administration of each SCFA or lactate for three days, caused phase changes in the peripheral clocks with stimulation timing dependency. However, this effect was not detected in cultured fibroblasts or cultured liver slices with SCFA applied to the culture medium, suggesting SCFA-induced indirect modulation of circadian clocks in vivo . Finally, cellobiose-containing diets facilitated SCFA production and refeeding-induced peripheral clock entrainment. SCFA oral gavage and prebiotic supplementation can facilitate peripheral clock adjustment, suggesting prebiotics as novel therapeutic candidates for misalignment.

Genomic imprinting, an epigenetic gene-marking phenomenon that occurs in the germline, leads to parental-origin-specific expression of a small subset of genes in mammals. Imprinting has a great impact on normal mammalian development, fetal growth, metabolism and adult behavior. The epigenetic imprints regarding the parental origin are established during male and female gametogenesis, passed to the zygote through fertilization, maintained throughout development and adult life, and erased in primordial germ cells before the new imprints are set. In this review, we focus on the recent discoveries on the mechanisms involved in the reprogramming and maintenance of the imprints. We also discuss the epigenetic changes that occur at imprinted loci in induced pluripotent stem cells.

Establishment of the DNA methylation landscape of mammalian oocytes, mediated by the DNMT3A-DNMT3L complex, is crucial for reproduction and development. In mouse oocytes, high levels of DNA methylation occur exclusively in the transcriptionally active regions, with moderate to low levels of methylation in other regions. Histone H3K36me3 mediates the high levels of methylation in the transcribed regions; however, it is unknown which histone mark guides the methylation in the other regions. Here, we show that, in mouse oocytes, H3K36me2 is highly enriched in the X chromosome and is broadly distributed across all autosomes. Upon H3K36me2 depletion, DNA methylation in moderately methylated regions is selectively affected, and a methylation pattern unique to the X chromosome is switched to an autosome-like pattern. Furthermore, we find that simultaneous depletion of H3K36me2 and H3K36me3 results in global hypomethylation, comparable to that of DNMT3A depletion. Therefore, the two histone marks jointly provide the chromatin platform essential for guiding DNMT3A-dependent DNA methylation in mouse oocytes. DNMT3A is known to methylate DNA at histone H3 lysine 36 (H3K36me3)-marked transcriptionally active regions in mouse oocytes. Here the authors show that DNMT3A is also guided by H3K36me2 to methylate broad domains in genic and intergenic loci, as well as on the X chromosome. These two histone marks together comprise the minimal chromatin signature for global DNA methylation in mouse oocytes.