The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming.

The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome, controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe however that the AT-hook regulates the intrinsic DNA-stimulated ATPase activity aside from promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (KM). The changes in ATP hydrolysis causes an equivalent change in nucleosome movement, confirming they are tightly coupled. The catalytic subunit's AT-hook is required in vivo for SWI/SNF remodeling activity in yeast and mouse embryonic stem cells. The AT-hook in SWI/SNF is required for transcription regulation and activation of stage-specific enhancers critical in cell lineage priming. Similarly, growth assays suggest the AT-hook is required in yeast SWI/SNF for activation of genes involved in amino acid biosynthesis and metabolizing ethanol. Our findings highlight the importance of studying SWI/SNF attenuation versus eliminating the catalytic subunit or completely shutting down its enzymatic activity.

Dinucleosome specificity and allosteric switch of the ISW1a ATP-dependent chromatin remodeler in transcription regulation.

Over the last 3 decades ATP-dependent chromatin remodelers have been thought to recognize chromatin at the level of single nucleosomes rather than higher-order organization of more than one nucleosome. We show the yeast ISW1a remodeler has such higher-order structural specificity, as manifested by large allosteric changes that activate the nucleosome remodeling and spacing activities of ISW1a when bound to dinucleosomes. Although the ATPase domain of Isw1 docks at the SHL2 position when ISW1a is bound to either mono- or di-nucleosomes, there are major differences in the interactions of the catalytic subunit Isw1 with the acidic pocket of nucleosomes and the accessory subunit Ioc3 with nucleosomal DNA. By mutational analysis and uncoupling of ISW1a's dinucleosome specificity, we find that dinucleosome recognition is required by ISW1a for proper chromatin organization at promoters; as well as transcription regulation in combination with the histone acetyltransferase NuA4 and histone H2A.Z exchanger SWR1.

Speciation of major and trace elements leached from coal fly ash and the kinetics involved.

The combustion of coal in thermal power plants may result in high concentrations of elements in the coal fly ash remaining that may be toxic to living organisms or pose a risk to the environment. This study was aimed at determining the concentrations of potentially toxic elements in coal fly ash leachates, in an attempt to simulate natural processes that influence the environment. Powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and elemental composition studies were employed to characterize the physicochemical properties of the parent coal fly ash. The effect of various leaching parameters, including the pH of leaching solutions, the volume ratio of leaching solutions to the mass of coal fly ash, leaching time and temperature, were investigated. Moreover, the kinetics of the leaching of toxic elements from coal fly ash was also investigated by considering that the leaching process is governed by dissolution. Zero order, pseudo-first order, pseudo-second order, power function, simple Elovich and parabolic diffusion kinetic models were used to evaluate the leaching process. The experimental results indicate that the pH and leaching time had the most significant effect on the leaching behavior of elements from coal fly ash.

INO80 exchanges H2A.Z for H2A by translocating on DNA proximal to histone dimers.

ATP-dependent chromatin remodellers modulate nucleosome dynamics by mobilizing or disassembling nucleosomes, as well as altering nucleosome composition. These chromatin remodellers generally function by translocating along nucleosomal DNA at the H3-H4 interface of nucleosomes. Here we show that, unlike other remodellers, INO80 translocates along DNA at the H2A-H2B interface of nucleosomes and persistently displaces DNA from the surface of H2A-H2B. DNA translocation and DNA torsional strain created near the entry site of nucleosomes by INO80 promotes both the mobilization of nucleosomes and the selective exchange of H2A.Z-H2B dimers out of nucleosomes and replacement by H2A-H2B dimers without any additional histone chaperones. We find that INO80 translocates and mobilizes H2A.Z-containing nucleosomes more efficiently than those containing H2A, partially accounting for the preference of INO80 to replace H2A.Z with H2A. Our data suggest that INO80 has a mechanism for dimer exchange that is distinct from other chromatin remodellers including its paralogue SWR1.

'We identify, discuss, act and promise to prevent similar deaths': a qualitative study of Ethiopia's Maternal Death Surveillance and Response system.

INTRODUCTION: Ethiopia introduced national Maternal Death Surveillance and Response (MDSR) in 2013 and is among the first sub-Saharan African countries to capture data on facility-based and community-based maternal deaths. We interviewed frontline MDSR implementers about their experiences of the first 2 years of MDSR, including perceptions of its introduction and outcomes for health services. METHODS: We conducted a qualitative case study in 4 zones in the largest regions, interviewing 69 key informants from regional, zonal, district and facility levels. RESULTS: A defining feature of Ethiopia's MDSR system is its integration within existing disease surveillance, with both benefits and challenges. Facilitators of the system's introduction were strong political support, alignment with broader health strategies and strong links across health system departments. Barriers included confusion around new responsibilities, high staff turnover and fear of legal repercussions. Stakeholders believed MDSR increased confidence in using local data to improve maternal health services and enhanced communication across the health system. CONCLUSIONS: MDSR systems take time to establish, encountering challenges in early implementation. Ensuring MDSR has a clear purpose, explicitly defined roles and responsibilities, and adequate supervisory support from the start will ensure it becomes embedded within the health system as routine practice rather than perceived as a stand-alone system. Countries planning to adopt or extend MDSR can learn from Ethiopia's experience, particularly the decision to make maternal mortality a weekly reportable condition within Public Health Emergency Management.

Loss of Snf5 Induces Formation of an Aberrant SWI/SNF Complex.

The SWI/SNF chromatin remodeling complex is highly conserved from yeast to human, and aberrant SWI/SNF complexes contribute to human disease. The Snf5/SMARCB1/INI1 subunit of SWI/SNF is a tumor suppressor frequently lost in pediatric rhabdoid cancers. We examined the effects of Snf5 loss on the composition, nucleosome binding, recruitment, and remodeling activities of yeast SWI/SNF. The Snf5 subunit is shown by crosslinking-mass spectrometry (CX-MS) and subunit deletion analysis to interact with the ATPase domain of Snf2 and to form a submodule consisting of Snf5, Swp82, and Taf14. Snf5 promotes binding of the Snf2 ATPase domain to nucleosomal DNA and enhances the catalytic and nucleosome remodeling activities of SWI/SNF. Snf5 is also required for SWI/SNF recruitment by acidic transcription factors. RNA-seq analysis suggests that both the recruitment and remodeling functions of Snf5 are required in vivo for SWI/SNF regulation of gene expression. Thus, loss of SNF5 alters the structure and function of SWI/SNF.