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Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a “reader” of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain mouse ESC pluripotency since knockdown of Npac causes mouse ESC differentiation. Depletion of Npac in mouse embryonic fibroblasts (MEFs) inhibits reprogramming efficiency. Furthermore, our Npac ChIP-seq results reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs. Interestingly, we find that Npac interacts with p-TEFb, RNA Pol II Ser2 and Ser5. Depletion of Npac disrupts transcriptional elongation of pluripotency genes Nanog and Rif1. Taken together, we propose that Npac is essential for transcriptional elongation of pluripotency genes by recruiting of p-TEFb and interacting with RNA Pol II Ser2 and Ser5.

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.

Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a “reader” of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain mouse ESC (mESC) pluripotency since knockdown of Npac causes mESC differentiation. Depletion of Npac in mouse embryonic fibroblasts (MEFs) inhibits reprogramming efficiency. Furthermore, our chromatin immunoprecipitation followed by sequencing (ChIP-seq) results of Npac reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs. Interestingly, we find that Npac interacts with positive transcription elongation factor b (p-TEFb), Ser2-phosphorylated RNA Pol II (RNA Pol II Ser2P), and Ser5-phosphorylated RNA Pol II (RNA Pol II Ser5P). Furthermore, depletion of Npac disrupts transcriptional elongation of the pluripotency genes Nanog and Rif1. Taken together, we propose that Npac is essential for the transcriptional elongation of pluripotency genes by recruiting p-TEFb and interacting with RNA Pol II Ser2P and Ser5P.

IntroductionHorizon scanning (HS) is an early health technology assessment (HTA) method for raising early awareness among policymakers of promising new and emerging health technologies. The Agency for Care Effectiveness (ACE) in Singapore established a HS system in 2019 to complement its HTA process. While the HS system initially focused on cell and gene therapies, this was expanded in 2020 to include medical technologies (MTs). This abstract focuses on the role of HS in nominating MTs for early evaluation to guide subsidy decisions, with the intention of avoiding challenges in altering deeply entrenched practices.MethodsThe ACE methodology for HS aligns with the core principles and methods of international best practice. Generally, MTs addressing national healthcare priorities are tracked. To identify topics for subsidy evaluation, the local registration status of an MT was used as the main selection criterion because of its proximity to the technology’s early diffusion into the healthcare system. MTs with regulatory approval were selected for HTA and subsidy consideration. All nominated technologies were checked against eligibility criteria for HTA and then assessed against a standard checklist for prioritizing HTA topics.ResultsAmong the 1,025 MTs tracked by the HS system, 89 were locally registered and nominated for HTA. Following eligibility assessment, 26 topics remained. After the prioritization exercise six topics were shortlisted. To date, two evaluations have been completed to guide subsidy decisions and four topics are undergoing evaluation. Notably, 16 of the 26 eligible topics were excluded due to a lack of sufficient evidence, in terms of both quantity and quality, for evaluation.ConclusionsHS can be a useful tool for identifying new MTs for evaluation and possible funding prior to further diffusion, but careful selection of the technologies is required to ensure a sufficient evidence base for evaluation. Moving forward, HS can also play a more active role in disinvestment of obsolete or low value health technologies.