Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation

Interactions Among Fire, Insects and Pathogens in Coniferous Forests of the Interior Western United States and Canada

1 Natural and recurring disturbances caused by fire, native forest insects and pathogens have interacted for millennia to create and maintain forests dominated by seral or pioneering species of conifers in the interior regions of the western United States and Canada. 2 Changes in fire suppression and other factors in the last century have altered the species composition and increased the density of trees in many western forests, leading to concomitant changes in how these three disturbance agents interact. 3 Two- and three-way interactions are reviewed that involve fire, insects and pathogens in these forests, including fire-induced pathogen infection and insect attack, the effects of tree mortality from insects and diseases on fuel accumulation, and efforts to model these interactions. 4 The emerging concern is highlighted regarding how the amount and distribution of bark beetle-caused tree mortality will be affected by large-scale restoration of these fire-adapted forest ecosystems via prescribed fire. 5 The effects of fire on soil insects and pathogens, and on biodiversity of ground-dwelling arthropods, are examined. 6 The effects of fire suppression on forest susceptibility to insects and pathogens, are discussed, as is the use of prescribed fire to control forest pests

Histone H3.3 beyond cancer: Germline mutations in<em> Histone 3 Family 3A</em> and 3B cause a previously unidentified neurodegenerative disorder in 46 patients.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation