N-methyladenosine (mA) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export, and translation. However, the precise mA regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc-finger protein, plays an important role in modulating RNA mA methylation in the nucleus. We show that knockdown of Zc3h13 in mouse embryonic stem cell significantly decreases global mA level on mRNA. Upon Zc3h13 knockdown, a great majority of WTAP, Virilizer, and Hakai translocate to the cytoplasm, suggesting that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA mA methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer, or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays a critical role in anchoring WTAP, Virilizer, and Hakai in the nucleus to facilitate mA methylation and to regulate mESC self-renewal.
SUMMARY
BS69 (aka ZMYND11) contains tandemly arranged PHD, BROMO and PWWP domains, which are chromatin recognition modalities. Here we show that BS69 selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3) via its chromatin-binding domains. We further identify BS69 association with RNA splicing regulators including the U5 snRNP components of the spliceosome such as EFTUD2. Remarkably, RNA-seq shows that BS69 mainly regulates intron retention (IR), which is the least well-understood RNA alternative splicing event in mammalian cells. Biochemical and genetic experiments demonstrate that BS69 promotes IR by antagonizing EFTUD2 through physical interactions. We further show that regulation of IR by BS69 also depends on its binding to H3K36me3-decorated chromatin. Taken together, our study identifies an H3.3K36me3-specific reader and a regulator of IR, and reveals a novel and unexpected role of BS69 in connecting histone H3.3K36me3 to regulated RNA splicing, providing significant new insights into chromatin regulation of pre-mRNA processing.
A 5-year prospective cohort study was conducted with 121,584 Chinese primary care patients with type 2 DM who were recruited between August 2009 and June 2011. Missing data were dealt with multiple imputations. After excluding patients with prior diabetes mellitus (DM)-related complications and one-to-one propensity score matching on all patient characteristics, 26,718 RAMP-DM participants and 26,718 matched usual care patients were followed up for a median time of 4.5 years. The effect of RAMP-DM on nine DM-related complications and all-cause mortality were evaluated using Cox regressions. The first incidence for each event was used for all models. Health service use was analyzed using negative binomial regressions. Subgroup analyses on different patient characteristics were performed.
RESULTSThe cumulative incidence of all events (DM-related complications and all-cause mortality) was 23.2% in the RAMP-DM group and 43.6% in the usual care group. RAMP-DM led to significantly greater reductions in cardiovascular disease (CVD) risk by 56.6% (95% CI 54.5, 58.6), microvascular complications by 11.9% (95% CI 7.0, 16.6), mortality by 66.1% (95% CI 64.3, 67.9), specialist attendance by 35.0% (95% CI 33.6, 36.4), emergency attendance by 41.2% (95% CI 39.8, 42.5), and hospitalizations by 58.5% (95% CI 57.2, 59.7). Patients with low baseline CVD risks benefitted the most from RAMP-DM, which decreased CVD and mortality risk by 60.4% (95% CI 51.8, 67.5) and 83.6% (95% CI 79.3, 87.0), respectively.
CONCLUSIONSThis naturalistic study highlighted the importance of early optimal DM control and risk factor management by risk stratification and multidisciplinary, protocol-driven, chronic disease model care to delay disease progression and prevent complications.
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