Histone

Histone succinylation directly inhibits Jumonji domain demethylases and stabilizes repressive chromatin states

Herein we uncover a relationship between histone succinylation and Jumonji (JmjC) domain-containing histone demethylases. We used quantitative proteomics and peptide pull-down assays to identify JmjC demethylases as candidate interactors with succinylated histone peptides. Succinyl-lysine peptides bind and inhibit the catalytic activity of JmjC demethylases in a dose-dependent manner.

Overexpression of Eaf1, a subunit of the NuA4 lysine acetyl transferase complex, rescues growth defects in the budding yeast H3K36M oncohistone model via histone H4 tail acetylation

Histone proteins are critical for regulating functions that occur at DNA, such as gene expression. Certain mutations in histone genes were characterized to drive oncogenesis, termed oncohistones, and one of the first identified oncohistones is H3K36M. While humans have a high copy number of H3 genes, making genetic engineering in cell lines challenging, budding yeast only have two H3 genes. Additionally, histone H3 shares 90% sequence identity between budding yeast and humans, making it a...

Molecular Basis of Histone H3 Reading and Writing by Legionella pneumophila SET Domain Lysine Methyltransferases

RomA and its highly conserved strain ortholog LegAS4 are SET and ankyrin domain-containing effector proteins of the intracellular bacterial pathogen Legionella pneumophila. These enzymes are secreted into host cells, where they translocate to the nucleus and methylate Lys14 in histone H3 (H3K14), a novel post-translation modification (PTM) that reprograms gene expression and promotes bacterial replication. To elucidate their H3K14 substrate specificity, we determined the crystal structures...

Nutrient-responsive and DAF-16/FoxO target H1 histone HIL-1 promotes resistance to starvation and bacterial pathogens in Caenorhabditis elegans

Insulin/IGF-1 signaling (IIS) mediates metabolic and developmental acclimation to stressful conditions including starvation. The transcription factor DAF-16/FoxO actuates many of the physiological effects of reduced IIS, yet the specific contributions of DAF-16 target genes to stress resistance remain poorly understood. We explore the function of C. elegans H1 linker histone HIL-1/H1.0, a DAF-16 target that is upregulated during starvation.

αKG-mediated carnitine synthesis drives DNA repair via histone acetylation

Jump-starting the T cell response in established tumors

Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results.

Nuclear confinement from matrix stiffness drives epigenomic reprogramming of gingival fibroblasts

Periodontal disease is characterized by progressive degradation of the gingival extracellular matrix and loss of the physical confinement it imposes on resident stromal cells. In human periodontal tissue, ECM collagen integrity is inversely correlated with facultative nuclear histone acetylation in stromal cells. We hypothesized that matrix stiffness directly coordinates an epigenomic shift in stromal cells.

SIRT7 regulates dosage compensation and safeguards the female X chromosome

Abstract Sirtuins are deacetylases implicated in stress responses and longevity in mammals1,2. Although their differential impact on disease for the two sexes has been noted3,4,5,6,7, the underlying reasons are unclear. Here, using Sirt7 as a model in mice, we examine the mechanisms leading to sex differences and find that Sirt7−/− female mice have decreased fitness throughout their lifespan.

A prognostic human brain network for diffuse midline glioma

Abstract Diffuse midline gliomas (DMGs) are near-universally lethal tumours of the childhood central nervous system1,2. In animal models, DMGs form brain-wide integrated networks through neuron-to-glioma synapses3,4,5,6 and glioma-to-glioma gap junctional coupling3. This extensive connectivity robustly promotes the growth and invasion of DMG3,4,5,6,7,8,9 and other glial malignancies10,11,12 through paracrine mechanisms and direct neuron-to-glioma synapses.

Mitochondria directly interact with the nuclear pore complex

Abstract Mitochondria regulate cellular processes through direct and indirect interactions with other organelles. A well-studied example has been contact with the endoplasmic reticulum at mitochondrial-associated endoplasmic reticulum membranes1, which control pathways including redox and calcium homeostasis2,3. Recent studies have also reported direct mitochondria–nuclear membrane contacts in cancer cells and yeast that promote pro-survival signalling4,5.