HDAC inhibitors cause site-specific chromatin remodeling at PU.1-bound enhancers in K562 cells

BACKGROUND: Small molecule inhibitors of histone deacetylases (HDACi) hold promise as anticancer agents for particular malignancies. However, clinical use is often confounded by toxicity, perhaps due to indiscriminate hyperacetylation of cellular proteins. Therefore, elucidating the mechanisms by which HDACi trigger differentiation, cell cycle arrest, or apoptosis of cancer cells could inform development of more targeted therapies. We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process. RESULTS: We identified several thousand specific regulatory elements [~10 % of total DNase I-hypersensitive (DHS) sites] that become significantly more or less accessible with sodium butyrate or suberanilohydroxamic acid treatment. Most of the differential DHS sites display hallmarks of enhancers, including being enriched for non-promoter regions, associating with nearby gene expression changes, and increasing luciferase reporter expression in K562 cells. Differential DHS sites were enriched for key hematopoietic lineage transcription factor motifs, including SPI1 (PU.1), a known pioneer factor. We found PU.1 increases binding at opened DHS sites with HDACi treatment by ChIP-seq, but PU.1 knockdown by shRNA fails to block the chromatin accessibility and expression changes. A machine-learning approach indicates H3K27me3 initially marks PU.1-bound sites that open with HDACi treatment, suggesting these sites are epigenetically poised. CONCLUSIONS: We find HDACi treatment of K562 cells results in site-specific chromatin remodeling at epigenetically poised regulatory elements. PU.1 shows evidence of a pioneer role in this process by marking poised enhancers but is not required for transcriptional activation.

A work-based research assessment of the impact of 'lean manufacturing' on health and safety education within an SME

Globalisation has had a major impact on the engineering industry as pacific Rim countries undercut manufacturing costs and provide a more cost-effective location for many businesses. Engineering in Nortehrn Ireland has mostly declined owing to increased competition from these countries. Engineering companies are now forced to streamline their production processes and employ cost-reducing practices in order to meet customer demands at reduced prices. This article aims to analyse the effects of one such streamlining endeavour which was first introduced after World War II in Japan- 'lean manufacturing' . 'Lean manufacturing' aims to reduce all wasteful activities within the production process in order to improve productivity, while reducing manufacturing costs. The work-based project under consideration was concerned with the impact 'lean manufacturing' may have on health and safety performance and education within an engineering company. The focus of the project was to determine through work-based research, and quantitative analysis, the employee perception on health and safety: has it changed (either positively or negatively), as a consequence of implementing 'lean manufacturing'.

Intellectual Property management in publicly funded R&D centres—A comparison of university-based and company-based research centres

Recent thinking on open innovation and the knowledge-based economy have stressed the importance of external knowledge sources in stimulating innovation. Policy-makers have recognised this, establishing publicly funded Centres of R&D Excellence with the objective of stimulating industry–science links and localised innovation spillovers. Here, we examine the contrasting IP management practices of a group of 18 university- and company-based R&D centres supported by the same regional programme. Our analysis covers all but one of the Centres supported by the programme and suggests marked contrasts between the IP strategies of the university-based and company-based centres. This suggests the potential for very different types of knowledge spillovers from publicly funded R&D centres based in different types of organisations, and a range of alternative policy approaches to the future funding of R&D centres depending on policy-makers’ objectives.