Reduction of Hox Gene Expression by Histone H1 Depletion

The evolutionarily conserved homeotic (Hox) genes are organized in clusters and expressed collinearly to specify body patterning during embryonic development. Chromatin reorganization and decompaction are intimately connected with Hox gene activation. Linker histone H1 plays a key role in facilitating folding of higher order chromatin structure. Previous studies have shown that deletion of three somatic H1 subtypes together leads to embryonic lethality and that H1c/H1d/H1e triple knockout (TKO) embryonic stem cells (ESCs) display bulk chromatin decompaction. To investigate the potential role of H1 and higher order chromatin folding in the regulation of Hox gene expression, we systematically analyzed the expression of all 39 Hox genes in triple H1 null mouse embryos and ESCs by quantitative RT-PCR. Surprisingly, we find that H1 depletion causes significant reduction in the expression of a broad range of Hox genes in embryos and ESCs. To examine if any of the three H1 subtypes (H1c, H1d and H1e) is responsible for decreased expression of Hox gene in triple-H1 null ESCs, we derived and characterized H1c−/−, H1d−/−, and H1e−/− single-H1 null ESCs. We show that deletion of individual H1 subtypes results in down-regulation of specific Hox genes in ESCs. Finally we demonstrate that, in triple-H1- and single-H1- null ESCs, the levels of H3K4 trimethylation (H3K4me3) and H3K27 trimethylation (H3K27me3) were affected at specific Hox genes with decreased expression. Our data demonstrate that marked reduction in total H1 levels causes significant reduction in both expression and the level of active histone mark H3K4me3 at many Hox genes and that individual H1 subtypes may also contribute to the regulation of specific Hox gene expression. We suggest possible mechanisms for such an unexpected role of histone H1 in Hox gene regulation

Promoting Sino-UK Collaboration on Developing Low Carbon and Sustainable Methodologies for Brownfields and Marginal Land Re-use in China

The authors are grateful to all partners of the SPF project which include a wide team of collaborators and advisors across China and UK for their useful discussions and contribution during the project. Ming Liu and Chris He (Department of Science, Technology & Innovation, British Consulate-General Guangzhou), Rongxia Liu and Xia Yang (Administrative Centre for China’s Agenda21), Kate Canning (Arup) and David Middleton (Department for Environment and Rural Affairs, UK) helped discussion and revision of the report. We acknowledge the financial support from the Foreign Common Office’s Prosperity Fund programme. We also are grateful to the contribution of the University of Brighton and the Land Trust who supported the PSRP case study development project and shared its findings with this project. This report is one of the outputs of the China Prosperity Strategic Programme Fund (SPF) on “Promoting Sino-UK collaboration on developing low carbon and sustainable methodologies for Brownfields and marginal land re-use in China” (project 16AG15)Rapid urbanisation and changes in land use resulting from industrial change has left a legacy of vast polluted industrial and commercial areas (also called brownfields) and marginal land areas. Recent evidence from the UK, EU and USA indicate that these land areas may have considerable potential for renewables production, for example from solar, wind or biomass. In parallel there are opportunities for carbon storage in rehabilitated soil, as well as substitution by the production of renewables. The UK is also leading the understanding in the wider parallel benefits that can be achieved from ecosystem services and public health benefits from improved provision of green space. These multiple services can be provided together, in synergy, from soft re-uses of post-industrial sites, and in this way the post-industrial regeneration areas in China should be seen as a major opportunity for new enterprise, society and the wider environment. The improving bankability of renewable energy projects, and the possibility of creating a voluntary carbon offset business, means that revenue streams may be sufficient to pay for ongoing land management over time as a profit generating activity. In terms of fastest benefit to UK PLC and China, the likelihood is that combination of renewable energies with “dual use” for habitat will provide both more readily commercial brownfield re-use opportunities for cities in China in the short term, and also create better carbon management opportunities, as well as a variety of wider sustainability benefits. Thus this type of re-uses will create a platform for rapid commercial exchange and development between Chinese and UK companies. Considering that China is preparing an action plan for managing soil pollution and remediation across the country estimated to be RMB 7tn which is equivalent to one-third of the national exchange reserves, this report on developing low carbon and sustainable methodologies for brownfields and marginal land re-use in China provides timely information that will support the decision making for sustainable remediation opportunities in China. The report is intended to serve as a tool and resource guide to stakeholders involved in land remediation willing to engage in sustainable remediation implementation for renewable energy and carbon management applications. It is intended to inform remediation stakeholders unfamiliar with sustainable remediation about the concept, practices, and available resources. The report capitalises on UK leadership positions on the sustainable rehabilitation of brownfields land (SURF-UK), the soft re-use of brownfields (e.g. for energy or amenity rather than buildings); effective end-use directed risk management for contaminated land, and sustainable remediation.Foreign Common Office’s Prosperity Fund programme SPF project 16AG1

Histone H1 Depletion Impairs Embryonic Stem Cell Differentiation

Pluripotent embryonic stem cells (ESCs) are known to possess a relatively open chromatin structure; yet, despite efforts to characterize the chromatin signatures of ESCs, the role of chromatin compaction in stem cell fate and function remains elusive. Linker histone H1 is important for higher-order chromatin folding and is essential for mammalian embryogenesis. To investigate the role of H1 and chromatin compaction in stem cell pluripotency and differentiation, we examine the differentiation of embryonic stem cells that are depleted of multiple H1 subtypes. H1c/H1d/H1e triple null ESCs are more resistant to spontaneous differentiation in adherent monolayer culture upon removal of leukemia inhibitory factor. Similarly, the majority of the triple-H1 null embryoid bodies (EBs) lack morphological structures representing the three germ layers and retain gene expression signatures characteristic of undifferentiated ESCs. Furthermore, upon neural differentiation of EBs, triple-H1 null cell cultures are deficient in neurite outgrowth and lack efficient activation of neural markers. Finally, we discover that triple-H1 null embryos and EBs fail to fully repress the expression of the pluripotency genes in comparison with wild-type controls and that H1 depletion impairs DNA methylation and changes of histone marks at promoter regions necessary for efficiently silencing pluripotency gene Oct4 during stem cell differentiation and embryogenesis. In summary, we demonstrate that H1 plays a critical role in pluripotent stem cell differentiation, and our results suggest that H1 and chromatin compaction may mediate pluripotent stem cell differentiation through epigenetic repression of the pluripotency genes

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Effects of high-intensity focused ultrasound combined with levonorgestrel-releasing intrauterine system on patients with adenomyosis

Abstract It is very important to treat adenomyosis which may cause infertility, menorrhagia, and dysmenorrhea for women at the reproductive age. High-intensity focused ultrasound (HIFU) is effective in destroying target tumor tissues without damaging the path of the ultrasound beam and surrounding normal tissues. The levonorgestrel-releasing intrauterine system (LN-IUS) is a medical system which is inserted into the uterine to provide medicinal treatment for temporary control of the symptoms caused by adenomyosis. This study was to investigate the effect of HIFU combined with the LN-IUS on adenomyosis. In the HIFU treatment, the parameters of the ultrasound were transmission frequency 0.8 MHz and input power 50–400 W (350 ± 30), and the temperature in the target tissue under these conditions would reach 60–100 °C (85 °C ± 6.3 °C). Size reduction and blood flow signal decrease were used to assess the effect of combined treatment. In this study, 131 patients with adenomyosis treated with HIFU combined with LN-IUS were retrospectively enrolled. The clinical and follow-up data were analyzed. After treatment, the volume of the uterine lesion was significantly decreased with an effective rate of 72.1%, and the adenomyosis blood flow signals were significantly reduced, with an effective rate of 71.3%. At six months, the menstrual cycle was significantly (P < 0.05) decreased from 31.4 ± 3.5 days before treatment to 28.6 ± 1.9 days, the menstrual period was significantly shortened from 7.9 ± 1.2 days before HIFU to 6.5 ± 1.3 days, and the menstrual volume was significantly (P < 0.05) decreased from 100 to 49% ± 13%. The serum hemoglobin significantly (P < 0.05) increased from 90.8 ± 6.2 g/L before treatment to 121.6 ± 10.8 g/L at six months for patients with anemia. Among seventy-two (92.3%) patients who finished the six-month follow-up, sixty-five (90.3%) patients had the dysmenorrhea completely relieved, and the other seven (9.7%) patients had only slight dysmenorrhea which did not affect their daily life. Adverse events occurred in 24 (18.3%) patients without causing severe consequences, including skin burns in two (1.5%) patients, skin swelling in four (3.1%), mild lower abdominal pain and low fever in 15 (11.5%), and subcutaneous induration in three (2.3%). Six months after treatment, no other serious side effects occurred in any patients with follow-up. In conclusions, the use of high-intensity focused ultrasound combined with the levonorgestrel-releasing intrauterine system for the treatment of adenomyosis is safe and effective even though the long-term effect remains to be confirmed

qChIP analysis of histone marks at <i>Hox</i> genes in WT and H1 TKO ESCs.

<p>The levels of H3K4me3 (A), H3K36me3 (B), H3K27me3 (C), and H3K9me3 (D) were analyzed by qChIP. Promoter regions of the indicated Hox genes were assayed, except for (B), for which gene body regions were analyzed. Dashed lines denote the highest signal level of control IgG qChIP. *: P<0.05, **: P<0.01, ***: P<0.001.</p

Reduction of <i>Hox</i> gene expression in H1 TKO embryos.

<p>(A) Relative expression of <i>Hox</i> genes with altered mRNA levels in H1 TKO embryos compared with WT. Down-regulated <i>Hox</i> genes are located in <i>HoxA</i> (i), <i>HoxC</i> (ii), and <i>HoxD</i> (iii) clusters. Expression levels of <i>Hox</i> genes were analyzed by qRT-PCR and normalized over <i>GAPDH</i> and represented as a fold change between H1 TKO and WT embryos at E8.5. *: P<0.05, **: P<0.01, ***: P<0.001. Error bars: S.D. (B) The schematic representation of <i>Hox</i> gene clusters with expression patterns in H1 TKO embryos compared with WT.</p

Primers for qChIP analysis.

<p>Primers for qChIP analysis.</p