Histone deacetylase inhibitors (HDIs) are a new class of drugs with significant antileukemic activity. To explore mechanisms of disease-specific HDI activity in acute myeloid leukaemia (AML), we have characterised expression of all 18 members of the histone deacetylase family in primary AML blasts and in four control cell types, namely CD34 þ progenitors from umbilical cord, either quiescent or cycling (post-culture), cycling CD34 þ progenitors from GCSF-stimulated adult donors and peripheral blood mononuclear cells. Only SIRT1 was consistently overexpressed (42 fold) in AML samples compared with all controls, while HDAC6 was overexpressed relative to adult, but not neo-natal cells. HDAC5 and SIRT4 were consistently underexpressed. AML blasts and cell lines, exposed to HDIs in culture, showed both histone hyperacetylation and, unexpectedly, specific hypermethylation of H3 lysine 4. Such treatment also modulated the pattern of HDAC expression, with strong induction of HDAC11 in all myeloid cells tested and with all inhibitors (valproate, butyrate, TSA, SAHA), and lesser, more selective, induction of HDAC9 and SIRT4. The distinct pattern of HDAC expression in AML and its response to HDIs is of relevance to the development of HDI-based therapeutic strategies and may contribute to observed patterns of clinical response and development of drug resistance.
Histones are subject to a wide variety of post-translational modifications that play a central role in gene activation and silencing. We have used histone modification-specific antibodies to demonstrate that two histone modifications involved in gene activation, histone H3 acetylation and H3 lysine 4 methylation, are functionally linked. This interaction, in which the extent of histone H3 acetylation determines both the abundance and the "degree" of H3K4 methylation, plays a major role in the epigenetic response to histone deacetylase inhibitors. A combination of in vivo knockdown experiments and in vitro methyltransferase assays shows that the abundance of H3K4 methylation is regulated by the activities of two opposing enzyme activities, the methyltransferase MLL4, which is stimulated by acetylated substrates, and a novel and as yet unidentified H3K4me3 demethylase.A growing body of evidence suggests that many different types of post-translational histone modifications play key roles in regulating gene expression and that some modifications at least are functionally inter-related (1). The linked deposition of distinct modifications can occur both on the same histone tail, e.g. H3S10 phosphorylation and H3K9 acetylation (2) or on different tails, e.g. H2A ubiquitination and H3 methylation (3), histone acetylation, and methylation (4, 5). Multiprotein complexes have been identified that are capable of depositing, or removing, different modifications in a coordinated manner (e.g. histone demethylase and deacetylase activity in coREST) (6). Similarly, binding proteins are sensitive to combinations of modifications; for example, HP1 binding to the H3 tail requires histone H3K9 methylation but is blocked by H3S10 phosphorylation and H3K14 acetylation (Ref. 7, although see Ref. 8).This suggests that epigenetic marks are not deposited or recognized in isolation but comprise a complex and inter-related collection of modifications at adjacent residues.The correlation between different histone modifications is particularly clear for histone H3 acetylation and the methylation of histone H3 lysine 4 (H3K4me). Mass spectrometric analysis of the cellular pool of histones indicates that this methyl mark is associated with histone H3 molecules containing high levels of acetylation (9). This is consistent with the observed co-localization of these marks, which show related distribution patterns both at a chromosome-wide level during X inactivation (10) and over the coding regions of individual genes (11,12). These correlations may arise due to physical links between histone-modifying enzymes such that they are co-recruited to the same loci. Both MLL1, a histone methyltransferase (HMT) 2 that can generate H3K4me marks (13), and Chd1, the chromatin remodeler that is subsequently recruited by this methyl mark, associate with histone acetyltransferase activities (14, 15), whereas the LSD1 complex that removes some of these methyl marks contains the histone deacetylases HDAC1 and HDAC2 (16). However, the interaction could also arise ...
As global demand for livestock products (such as meat, milk and eggs) is expected to double by 2050, necessary increases to future production must be reconciled with negative environmental impacts that livestock cause. This paper describes the LivestockPlus concept and demonstrates how the sowing of improved forages can lead to the sustainable intensification of mixed crop-forage-livestock-tree systems in the tropics by producing multiple social, economic and environmental benefits. Sustainable intensification not only improves the productivity of tropical forage-based systems but also reduces the ecological footprint of livestock production and generates a diversity of ecosystem services (ES) such as improved soil quality and reduced erosion, sedimentation and greenhouse gas (GHG) emissions. Integrating improved grass and legume forages into mixed production systems (crop-livestock, tree-livestock, crop-tree-livestock) can restore degraded lands and enhance system resilience to drought and waterlogging associated with climate change. When properly managed tropical forages accumulate large amounts of carbon in soil, fix atmospheric nitrogen (legumes), inhibit nitrification in soil and reduce nitrous oxide emissions (grasses), and reduce GHG emissions per unit livestock product.The LivestockPlus concept is defined as the sustainable intensification of forage-based systems, which is based on 3 interrelated intensification processes: genetic intensification -the development and use of superior grass and legume www.tropicalgrasslands.info cultivars for increased livestock productivity; ecological intensification -the development and application of improved farm and natural resource management practices; and socio-economic intensification -the improvement of local and national institutions and policies, which enable refinements of technologies and support their enduring use. Increases in livestock productivity will require coordinated efforts to develop supportive government, non-government organization and private sector policies that foster investments and fair market compensation for both the products and ES provided. Effective research-for-development efforts that promote agricultural and environmental benefits of foragebased systems can contribute towards implemention of LivestockPlus across a variety of geographic, political and socio-economic contexts. ResumenDe la misma manera que la demanda global de productos pecuarios (carne, leche, huevos) se duplicará para 2050, se espera que las producciones futuras tengan en cuenta los efectos ambientales negativos ocasionados por este sector. En este documento se describe el concepto LivestockPlus y se demuestra cómo en el trópico los forrajes mejorados pueden llevar a la intensificación sostenible de sistemas de producción mixta que integran forrajes/ganadería y cultivos y/o árboles, produciendo múltiples beneficios sociales, económicos y ambientales. La intensificación sostenible no sólo incrementa la productividad de los sistemas tropicales basados en forra...
The impact of changing climate on terrestrial and underwater archaeological sites, historic buildings, and cultural landscapes can be examined through quantitatively-based analyses encompassing large data samples and broad geographic and temporal scales. The Digital Index of North American Archaeology (DINAA) is a multi-institutional collaboration that allows researchers online access to linked heritage data from multiple sources and data sets. The effects of sea-level rise and concomitant human population relocation is examined using a sample from nine states encompassing much of the Gulf and Atlantic coasts of the southeastern United States. A 1 m rise in sea-level will result in the loss of over >13,000 recorded historic and prehistoric archaeological sites, as well as over 1000 locations currently eligible for inclusion on the National Register of Historic Places (NRHP), encompassing archaeological sites, standing structures, and other cultural properties. These numbers increase substantially with each additional 1 m rise in sea level, with >32,000 archaeological sites and >2400 NRHP properties lost should a 5 m rise occur. Many more unrecorded archaeological and historic sites will also be lost as large areas of the landscape are flooded. The displacement of millions of people due to rising seas will cause additional impacts where these populations resettle. Sea level rise will thus result in the loss of much of the record of human habitation of the coastal margin in the Southeast within the next one to two centuries, and the numbers indicate the magnitude of the impact on the archaeological record globally. Construction of large linked data sets is essential to developing procedures for sampling, triage, and mitigation of these impacts.
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