Highlights d SETD5 is an epigenetic driver of pancreatic cancer resistance to MEK1/2 inhibition d SETD5 has no intrinsic methylation activity on histones, including at H3 lysine 36 d A SETD5 co-repressor complex regulates a network of drug resistance pathways d Co-targeting of MEK1/2 and the SETD5 complex results in sustained tumor inhibition

HIV infection often involves the development of AIDS-related dementia complex, a variety of neurologic, neuropsychologic, and neuropathologic impairments. A possible contributor to AIDS-related dementia complex is the HIV envelope glycoprotein gp120, which damages neurons via a complex glutamate receptor-and calcium-dependent cascade. We demonstrate an endocrine modulation of the deleterious effects of gp120 in primary hippocampal and cortical cultures. Specifically, we observe that gp120-induced calcium mobilization and neurotoxicity are exacerbated by glucocorticoids, the adrenal steroids secreted during stress. Importantly, this deleterious synergy can occur between gp120 and synthetic glucocorticoids (such as prednisone or dexamethasone) that are used clinically in high concentrations to treat severe cases of the Pneumocystis carinii pneumonia typical of HIV infection. Conversely, we also observe that estradiol protects neurons from the deleterious actions of gp120, reducing toxicity and calcium mobilization.

Overexpression of bcl-2 protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.

Nuc-MS characterizes histone modifications and variants directly from intact endogenous nucleosomes. Preserving whole nucleosome particles enables precise interrogation of their protein content, as for H3.3-containing nucleosomes which had 6fold co-enrichment of variant H2A.Z over bulk chromatin. Nuc-MS, validated by ChIPseq, showed co-occurrence of oncogenic H3.3K27M with euchromatic marks (e.g., H4K16ac and >15-fold enrichment of H3K79me2). By capturing the entire epigenetic landscape, Nuc-MS provides a new, quantitative readout of nucleosome-level biology. MainThe post-translational modifications (PTMs) decorating the four core histones in an intact nucleosome encode information for nuclear effectors that trigger defined cellular events critical to health and disease. [1][2][3][4] For decades, affinity reagents, mass spectrometry and proteomics have played key roles in characterizing the many histone isoforms and PTMs involved in epigenetic regulation. [5][6][7] However, the standard practice of relying on digestion 8 and/or denaturation 5 removes the linkage between modifications and their nucleosomes of origin (Fig. 1a, at left). By digesting histone mixtures into small peptides, correlations among PTMs are forfeited, precluding strong assertions about the original composition of the intact histone. Similarly, when a nucleosome population is denatured, information about co-localization of histone isoforms and PTMs within the same nucleosome particle is lost. This inference problem diminishes our understanding of the organization and impact of co-occurring modifications, isoforms and mutations in epigenetics and disease pathogenesis. 9,10

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