G1 length dictates heterochromatin landscape.

Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells, however, the underlying mechanism for this observation has been unknown. Because H3K27me3 levels are diluted two-fold in every round of replication and then restored through the rest of the cycle, we reasoned that the cell cycle length could determine the time available for setting total H3K27me3 levels. Here, we demonstrate that a fast cell cycle sets low levels of H3K27me3 in serum-grown murine embryonic stem cells (mESCs). Extending the G1 phase leads to an increase in global H3K27me3 in mESCs due to the formation of de novo Polycomb domains, and the length of the G1/S block correlates with the extent of gain in H3K27me3, arguing that levels of the modification depend on the time available between successive rounds of replication. Similarly, accelerating the cell cycle in HEK293 cells decreases H3K27me3 levels. Finally, we applied this principle in tumor cells that, due to the dominant negative effect of the sub-stoichiometric H3K27M mutant, have reduced H3K27me3. Here, extending G1 using Palbociclib increased H3K27me3 levels, pointing to an unexpected means to rescue the effect of oncohistones. Our results suggest cell cycle length as a universal mechanism to modulate heterochromatin formation and, thus, cellular identity.

A biomarker panel for risk of early respiratory failure following hematopoietic cell transplantation.

Plasma biomarkers associated with respiratory failure (RF) following hematopoietic cell transplantation (HCT) have not been identified. Therefore, we aimed to validate early (7 and 14 days post-HCT) risk biomarkers for RF. Using tandem mass spectrometry, we compared plasma obtained at day 14 post-HCT from 15 patients with RF and 15 patients without RF. Six candidate proteins, from this discovery cohort or identified in the literature, were measured by enzyme-linked immunosorbent assay in day-7 and day-14 post-HCT samples from the training (n = 213) and validation (n = 119) cohorts. Cox proportional-hazard analyses with biomarkers dichotomized by Youden's index, as well as landmark analyses to determine the association between biomarkers and RF, were performed. Of the 6 markers, Stimulation-2 (ST2), WAP 4-disulfide core domain protein 2 (WFDC2), interleukin-6 (IL-6), and tumor necrosis factor receptor 1 (TNFR1), measured at day 14 post-HCT, had the most significant association with an increased risk for RF in the training cohort (ST2: hazard ratio [HR], 4.5, P = .004; WFDC2: HR, 4.2, P = .010; IL-6: HR, 6.9, P < .001; and TFNR1: HR, 6.1, P < .001) and in the validation cohort (ST2: HR, 23.2, P = .013; WFDC2: HR, 18.2, P = .019; IL-6: HR, 12.2, P = .014; and TFNR1: HR, 16.1, P = .001) after adjusting for the conditioning regimen. Using cause-specific landmark analyses, including days 7 and 14, high plasma levels of ST2, WFDC2, IL-6, and TNFR1 were associated with an increased HR for RF in the training and validation cohorts. These biomarkers were also predictive of mortality from RF. ST2, WFDC2, IL-6 and TNFR1 levels measured early posttransplantation improve risk stratification for RF and its related mortality.