Summary Dysregulation of O‐GlcNAc modification catalyzed by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer’s disease. Here we found that natural aging in wild‐type mice was marked by a decrease in OGA and OGT protein levels and an increase in O‐GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O‐GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum‐stimulated cell cycle entry induced increased O‐GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O‐GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O‐GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O‐GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.

The Mis18 complex has been identified as a critical factor for the centromeric localization of a histone H3 variant, centromeric protein A (CENP-A), which is responsible for the specification of centromere identity in the chromosome. However, the functional role of Mis18 complex is largely unknown. Here, we generated Mis18a conditional knockout mice and found that Mis18a deficiency resulted in lethality at early embryonic stage with severe defects in chromosome segregation caused by mislocalization of CENP-A. Further, we demonstrate Mis18a's crucial role for epigenetic regulation of centromeric chromatin by reinforcing centromeric localization of DNMT3A/3B. Mis18a interacts with DNMT3A/3B, and this interaction is critical for maintaining DNA methylation and hence regulating epigenetic states of centromeric chromatin. Mis18a deficiency led to reduced DNA methylation, altered histone modifications, and uncontrolled noncoding transcripts in centromere region by decreased DNMT3A/3B enrichment. Together, our findings uncover the functional mechanism of Mis18a and its pivotal role in mammalian cell cycle.

The retinoic acid receptor-related orphan receptor-α (RORα) is an important regulator of various biological processes, including cerebellum development, circadian rhythm and cancer. Here, we show that hepatic RORα controls lipid homeostasis by negatively regulating transcriptional activity of peroxisome proliferators-activated receptor-γ (PPARγ) that mediates hepatic lipid metabolism. Liver-specific Rorα-deficient mice develop hepatic steatosis, obesity and insulin resistance when challenged with a high-fat diet (HFD). Global transcriptome analysis reveals that liver-specific deletion of Rorα leads to the dysregulation of PPARγ signaling and increases hepatic glucose and lipid metabolism. RORα specifically binds and recruits histone deacetylase 3 (HDAC3) to PPARγ target promoters for the transcriptional repression of PPARγ. PPARγ antagonism restores metabolic homeostasis in HFD-fed liver-specific Rorα deficient mice. Our data indicate that RORα has a pivotal role in the regulation of hepatic lipid homeostasis. Therapeutic strategies designed to modulate RORα activity may be beneficial for the treatment of metabolic disorders.

During the process of B cell development, transcription factors, such as E2A and Ebf1, have been known to play key roles. Although transcription factors and chromatin regulators work in concert to direct the expression of B lineage-specific genes, little is known about the involvement of regulators for chromatin structure during B lymphopoiesis. In this article, we show that deletion of Srg3/mBaf155, a scaffold subunit of the SWI/SNF-like BAF complex, in the hematopoietic lineage caused defects at both the common lymphoid progenitor stage and the transition from pre–pro-B to early pro-B cells due to failures in the expression of B lineage-specific genes, such as Ebf1 and Il7ra, and their downstream target genes. Moreover, mice that were deficient in the expression of Brg1, a subunit of the complex with ATPase activity, also showed defects in early B cell development. We also found that the expression of Ebf1 and Il7ra is directly regulated by the SWI/SNF-like BAF complex. Thus, our results suggest that the SWI/SNF-like BAF complex facilitates early B cell development by regulating the expression of B lineage-specific genes.

A route to the top-down fabrication of highly ordered and aligned silicon nanowire (SiNW) arrays with degenerately doped source/drain regions from a bulk Si wafer is presented. In this approach, freestanding n- and p-SiNWs with an inverted triangular cross section are obtained using conventional photolithography, crystal orientation dependent wet etching, size reduction oxidation, and ion implantation doping. Based on these n- and p-SiNWs transferred onto a plastic substrate, simple SiNW-based complementary metal-oxide-semiconductor (CMOS) inverters are constructed for the possible applications of these SiNW arrays in integrated circuits on plastic. The static voltage transfer characteristic of the SiNW-based CMOS inverter exhibits a voltage gain of ∼9 V/V and a transition of 0.32 V at an operating voltage of 1.5 V with a full output voltage swing between 0 V and V(DD), and its mechnical bendability indicates good fatigue properties for potential applications of flexible electronics. This novel top-down approach is fully compatible with the current state-of-the-art Si-based CMOS technologies and, therefore, offers greater flexibility in device design for both high-performance and low-power functionality.

Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).

In this study, we present the steep switching characteristics of bendable feedback field-effect transistors (FBFETs) consisting of p(+)-i-n(+) Si nanowires (NWs) and dual-top-gate structures. As a result of a positive feedback loop in the intrinsic channel region, our FBFET features the outstanding switching characteristics of an on/off current ratio of approximately 10(6), and point subthreshold swings (SSs) of 18-19 mV/dec in the n-channel operation mode and of 10-23 mV/dec in the p-channel operation mode. Not only can these devices operate in n- or p-channel modes, their switching characteristics can also be modulated by adjusting the gate biases. Moreover, the device maintains its steep SS characteristics, even when the substrate is bent. This study demonstrates the promising potential of bendable NW FBFETs for use as low-power components in integrated circuits or memory devices.

TopBP1 plays important roles in chromosome replication, DNA damage response, and other cellular regulatory functions in vertebrates. Although the roles of TopBP1 have been studied mostly in cancer cell lines, its physiological function remains unclear in mice and untransformed cells. We generated conditional knock-out mice in which exons 5 and 6 of the TopBP1 gene are flanked by loxP sequences. Although TopBP1-deficient embryos developed to the blastocyst stage, no homozygous mutant embryos were recovered at E8.5 or beyond, and completely resorbed embryos were frequent at E7.5, indicating that mutant embryos tend to die at the periimplantation stage. This finding indicated that TopBP1 is essential for cell proliferation during early embryogenesis. Ablation of TopBP1 in TopBP1 flox/flox mouse embryonic fibroblasts and 3T3 cells using Cre recombinase-expressing retrovirus arrests cell cycle progression at the G 1 , S, and G 2 /M phases. The TopBP1-ablated mouse cells exhibit phosphorylation of H2AX and Chk2, indicating that the cells contain DNA breaks. The TopBP1-ablated mouse cells enter cellular senescence. Although RNA interference-mediated knockdown of TopBP1 induced cellular senescence in human primary cells, it induced apoptosis in cancer cells. Therefore, TopBP1 deficiency in untransformed mouse and human primary cells induces cellular senescence rather than apoptosis. These results indicate that TopBP1 is essential for cell proliferation and maintenance of chromosomal integrity.TopBP1 5 is conserved in eukaryotes and contains repeats of BRCA1 carboxyl-terminal motifs, which are found in proteins involved in DNA repair and regulation of cell cycle checkpoints (1-6). Recent findings indicate that TopBP1 participates in the loading of Cdc45 for the assembly of the preinitiation complex that is necessary for chromosomal DNA replication (7-11). Knockdown of TopBP1 in human cancer cells showed that TopBP1 is necessary for the activation of cyclin E/CDK2 and Cdc7/Dbf4 kinases as well as the loading of DNA polymerase onto chromatin (12). In response to replication fork stalling or DNA damage, TopBP1 functions as an activator of the ATR⅐ATRIP complex by binding to Rad9 of the Rad9⅐Hus1⅐Rad1 complex (13,14). The activated ATR phosphorylates Chk1, Nbs1, Smc1, and H2AX (15-18). TopBP1 also mediates ATR-mediated Chk1 activation by facilitating the interaction of claspin and Chk1 (19,20). Furthermore, association of TopBP1 with NBS1 is involved in double-stranded DNA break-induced homologous recombination repair (21). Therefore, TopBP1 plays crucial roles in the maintenance of genomic integrity.TopBP1 regulates gene expression. Binding of TopBP1 to E2F1 represses E2F1 proapoptotic activity by recruiting the Brg1⅐Brm chromatin remodeling complex (22). TopBP1 also binds to the DNA binding domain of p53 and inhibits the promoter binding activity of this protein (23). Therefore, TopBP1 depletion derepresses the proapoptotic activity of p53 and E2F1 and induces cellular apoptosis. In addition, TopBP1 represses Miz-1 express...