H2A Ubiquitination Alters H3-tail Dynamics on Linker-DNA to Enhance H3K27 Methylation.

Polycomb repressive complex 1 (PRC1) and PRC2 are responsible for epigenetic gene regulation. PRC1 ubiquitinates histone H2A (H2Aub), which subsequently promotes PRC2 to introduce the H3 lysine 27 tri-methyl (H3K27me3) repressive chromatin mark. Although this mechanism provides a link between the two key transcriptional repressors, PRC1 and PRC2, it is unknown how histone-tail dynamics contribute to this process. Here, we have examined the effect of H2A ubiquitination and linker-DNA on H3-tail dynamics and H3K27 methylation by PRC2. In naïve nucleosomes, the H3-tail dynamically contacts linker DNA in addition to core DNA, and the linker-DNA is as important for H3K27 methylation as H2A ubiquitination. H2A ubiquitination alters contacts between the H3-tail and DNA to improve the methyltransferase activity of the PRC2-AEBP2-JARID2 complex. Collectively, our data support a model in which H2A ubiquitination by PRC1 synergizes with linker-DNA to hold H3 histone tails poised for their methylation by PRC2-AEBP2-JARID2.

Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release.

The metazoan-specific acetyltransferase p300/CBP is involved in activating signal-induced, enhancer-mediated transcription of cell-type-specific genes. However, the global kinetics and mechanisms of p300/CBP activity-dependent transcription activation remain poorly understood. We performed genome-wide, time-resolved analyses to show that enhancers and super-enhancers are dynamically activated through p300/CBP-catalyzed acetylation, deactivated by the opposing deacetylase activity, and kinetic acetylation directly contributes to maintaining cell identity at very rapid (minutes) timescales. The acetyltransferase activity is dispensable for the recruitment of p300/CBP and transcription factors but essential for promoting the recruitment of TFIID and RNAPII at virtually all enhancers and enhancer-regulated genes. This identifies pre-initiation complex assembly as a dynamically controlled step in the transcription cycle and reveals p300/CBP-catalyzed acetylation as the signal that specifically promotes transcription initiation at enhancer-regulated genes. We propose that p300/CBP activity uses a "recruit-and-release" mechanism to simultaneously promote RNAPII recruitment and pause release and thereby enables kinetic activation of enhancer-mediated transcription.

Physical inactivity associated with the risk of non-communicable diseases in Japanese working mothers with young children: A cross-sectional study in Nagano city, Japan.

Physical activity helps to prevent the development of chronic non-communicable diseases. However, childbearing generally reduces parents' level of physical activity, particularly in mothers. Therefore, mothers with young children generally have lower levels of physical activity and have a higher risk of developing non-communicable diseases. The aim of the present study was to examine this risk in Japanese working mothers with young children. A cross-sectional study was conducted in four nursery schools in Nagano city, Japan. All mothers were asked to complete a questionnaire regarding abnormal findings at their proximate annual medical examination, and were asked to record their normal physical activity. A total of 182 mothers completed the questionnaires, and 36 reported having abnormal findings (ABN group). Mothers in the ABN group were significantly older than those without abnormal findings (NOR; P=0.043). No significant differences in physical activity were observed between the two groups; however, mothers in the ABN group spent a significantly longer time sitting than those in the NOR group (P=0.028). Regarding socioeconomic characteristics, mothers in the ABN group had a significantly higher educational background (P=0.040) and a higher annual family income (P<0.001) compared with those in the NOR group, and significantly more mothers held full-time jobs (55.9 vs. 36.0%; P=0.005). Full-time working mothers typically had a significantly higher family income (P<0.001) and spent a significantly longer time sitting (P<0.001) compared with mothers in part-time and other work. Therefore, the results of the present study suggest that sedentary lifestyles, namely the amount of time spent sitting, may increase the risk of Japanese working mothers with young children developing non-communicable diseases.

Guanine- 5-carboxylcytosine base pairs mimic mismatches during DNA replication.

The genetic information encoded in genomes must be faithfully replicated and transmitted to daughter cells. The recent discovery of consecutive DNA conversions by TET family proteins of 5-methylcytosine into 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (5caC) suggests these modified cytosines act as DNA lesions, which could threaten genome integrity. Here, we have shown that although 5caC pairs with guanine during DNA replication in vitro, G·5caC pairs stimulated DNA polymerase exonuclease activity and were recognized by the mismatch repair (MMR) proteins. Knockdown of thymine DNA glycosylase increased 5caC in genome, affected cell proliferation via MMR, indicating MMR is a novel reader for 5caC. These results suggest the epigenetic modification products of 5caC behave as DNA lesions.