Pyrido- and benzisothiazolones as inhibitors of histone acetyltransferases (HATs)

Histone acetyltransferases (HATs) are interesting targets for the treatment of cancer and HIV infections but reports on selective inhibitors are very limited. Here we report structure–activity studies of pyrido- and benzisothiazolones in the in vitro inhibition of histone acetyltransferases, namely PCAF, CBP, Gcn5 and p300 using a heterogeneous assay with antibody mediated quantitation of the acetylation of a peptidic substrate. Dependent on the chemical structure distinct subtype selectivity profiles can be obtained. While N-aryl derivatives usually are rather pan-HAT inhibitors, N-alkyl derivatives show mostly a preference for CBP/p300. Selected compounds were also shown to be inhibitors of MOF. The best inhibitors show submicromolar inhibition of CBP. Selected compounds affect growth of HL-60 leukemic cells and LNCaP prostate carcinoma cells with higher potency on the leukemic cells. Target engagement was shown with reduction of histone acetylation in LNCaP cells

Dynamic Regulation of Tgf-B Signaling by Tif1γ: A Computational Approach

TIF1γ (Transcriptional Intermediary Factor 1 γ) has been implicated in Smad-dependent signaling by Transforming Growth Factor beta (TGF-β). Paradoxically, TIF1γ functions both as a transcriptional repressor or as an alternative transcription factor that promotes TGF-β signaling. Using ordinary differential-equation models, we have investigated the effect of TIF1γ on the dynamics of TGF-β signaling. An integrative model that includes the formation of transient TIF1γ-Smad2-Smad4 ternary complexes is the only one that can account for TGF-β signaling compatible with the different observations reported for TIF1γ. In addition, our model predicts that varying TIF1γ/Smad4 ratios play a critical role in the modulation of the transcriptional signal induced by TGF-β, especially for short stimulation times that mediate higher threshold responses. Chromatin immunoprecipitation analyses and quantification of the expression of TGF-β target genes as a function TIF1γ/Smad4 ratios fully validate this hypothesis. Our integrative model, which successfully unifies the seemingly opposite roles of TIF1γ, also reveals how changing TIF1γ/Smad4 ratios affect the cellular response to stimulation by TGF-β, accounting for a highly graded determination of cell fate

Temporal expression of MOF acetyltransferase primes transcription factor networks for erythroid fate

Self-renewal and differentiation of hematopoietic stem cells (HSCs) are orchestrated by the combinatorial action of transcription factors and epigenetic regulators. Here, we have explored the mechanism by which histone H4 lysine 16 acetyltransferase MOF regulates erythropoiesis. Single-cell RNA sequencing and chromatin immunoprecipitation sequencing uncovered that MOF influences erythroid trajectory by dynamic recruitment to chromatin and its haploinsufficiency causes accumulation of a transient HSC population. A regulatory network consisting of MOF, RUNX1, and GFI1B is critical for erythroid fate commitment. GFI1B acts as a Mof activator which is necessary and sufficient for cell type-specific induction of Mof expression. Plasticity of Mof-depleted HSCs can be rescued by expression of a downstream effector, Gata1, or by rebalancing acetylation via a histone deacetylase inhibitor. Accurate timing and dosage of Mof expression act as a rheostat for the feedforward transcription factor network that safeguards progression along the erythroid fate

Structural control of weathering processes within exhumed granitoids: Compartmentalisation of geophysical properties by faults and fractures

International audienceIn the latter stages of exhumation processes, rocks undergo weathering. Weathering halos have been described in the vicinity of structures such as faults, veins or dykes, with a lateral size gradually narrowing with depth, symmetrically around the structures. In this paper, we describe the geophysical characterisation of such alteration patterns on two granitoid outcrops of the Catalan Coastal Ranges (Spain), each of which is affected by one major fault, as well as minor faults and fractures. Seismic, electric and ground penetrating radar surveys were carried out to map the spatial distribution of P-wave velocity, electrical resistivity and to identify reflectors of electromagnetic waves. The analysis of this multi-method and complementary dataset revealed that, at shallow depth, geophysical properties of the materials are compartmentalised and asymmetric with respect to major and subsidiary faults affecting the rock mass. This compartmentalisation and asymmetry both tend to attenuate with depth, whereas the effect of weathering is more symmetric with respect to the major structure of the outcrops. We interpret such compartmentalisation as resulting from the role of hydraulic and mechanical boundaries played by subsidiary faults, which tend to govern both the chemical and physical alterations involved in weathering. Thus, the smoothly narrowing halo model is not always accurate, as weathering halos can be strongly asymmetrical and present highly irregular contours delimiting sharp contrasts of geophysical properties. These results should be considered when investigating and modelling fluid storage and transfer in top crystalline rock settings for groundwater applications, hydrocarbon or geothermal reservoirs, as well as mineral deposits

Reply to comment of A.D. Chave on ‘Robust error on magnetotelluric impedance estimates’ by P. Wawrzyniak, P. Sailhac and G. Marquis, Geophysical Prospecting , 61 , 533-546

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The NSL complex maintains nuclear architecture stability via lamin A/C acetylation

While nuclear lamina abnormalities are hallmarks of human diseases, their interplay with epigenetic regulators and precise epigenetic landscape remain poorly understood. Here, we show that loss of the lysine acetyltransferase MOF or its associated NSL-complex members KANSL2 or KANSL3 leads to a stochastic accumulation of nuclear abnormalities with genomic instability patterns including chromothripsis. SILAC-based MOF and KANSL2 acetylomes identified lamin A/C as an acetylation target of MOF. HDAC inhibition or acetylation-mimicking lamin A derivatives rescue nuclear abnormalities observed in MOF-deficient cells. Mechanistically, loss of lamin A/C acetylation resulted in its increased solubility, defective phosphorylation dynamics and impaired nuclear mechanostability. We found that nuclear abnormalities include EZH2-dependent histone H3 Lys 27 trimethylation and loss of nascent transcription. We term this altered epigenetic landscape “heterochromatin enrichment in nuclear abnormalities” (HENA). Collectively, the NSL-complex-dependent lamin A/C acetylation provides a mechanism that maintains nuclear architecture and genome integrity

Neural metabolic imbalance induced by MOF dysfunction triggers pericyte activation and breakdown of vasculature

Mutations in chromatin-modifying complexes and metabolic enzymes commonly underlie complex human developmental syn-dromes affecting multiple organs. A major challenge is to determine how disease-causing genetic lesions cause deregulation of homeostasis in unique cell types. Here we show that neural-specific depletion of three members of the non-specific lethal (NSL) chromatin complex—Mof, Kansl2 or Kansl3—unexpectedly leads to severe vascular defects and brain haemorrhaging. Deregulation of the epigenetic landscape induced by the loss of the NSL complex in neural cells causes widespread metabolic defects, including an accumulation of free long-chain fatty acids (LCFAs). Free LCFAs induce a Toll-like receptor 4 (TLR4)–NFκB-dependent pro-inflammatory signalling cascade in neighbouring vascular pericytes that is rescued by TLR4 inhibition. Pericytes display functional changes in response to LCFA-induced activation that result in vascular breakdown. Our work estab-lishes that neurovascular function is determined by the neural metabolic environment