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Trimethylated histone H3 lysine 27 (H3K27me3) regulates gene repression, cell-fate determination and differentiation. We report that a conserved bromo-adjacent homology (BAH) module of BAHCC1 (BAHCC1BAH) 'recognizes' H3K27me3 specifically and enforces silencing of H3K27me3-demarcated genes in mammalian cells. Biochemical, structural and integrated chromatin immunoprecipitation-sequencing-based analyses demonstrate that direct readout of H3K27me3 by BAHCC1 is achieved through a hydrophobic trimethyl-L-lysine-binding 'cage' formed by BAHCC1BAH, mediating colocalization of BAHCC1 and H3K27me3-marked genes. BAHCC1 is highly expressed in human acute leukemia and interacts with transcriptional corepressors. In leukemia, depletion of BAHCC1, or disruption of the BAHCC1BAH-H3K27me3 interaction, causes derepression of H3K27me3-targeted genes that are involved in tumor suppression and cell differentiation, leading to suppression of oncogenesis. In mice, introduction of a germline mutation at Bahcc1 to disrupt its H3K27me3 engagement causes partial postnatal lethality, supporting a role in development. This study identifies an H3K27me3-directed transduction pathway in mammals that relies on a conserved BAH 'reader'.

The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR--tandemly dispersed repeats of phenylalanine and glycine residues.sup.1,2. However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98-HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias.sup.1,2, are essential for establishing liquid-liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98-HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad 'super-enhancer'-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein.sup.3,4, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98-HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases.sup.1,2,4-7, this mechanism can potentially be generalized to many malignant and pathological settings. The NUP98-HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping., Author(s): Jeong Hyun Ahn [sup.1] [sup.2] , Eric S. Davis [sup.3] , Timothy A. Daugird [sup.4] , Shuai Zhao [sup.1] [sup.2] , Ivana Yoseli Quiroga [sup.5] , Hidetaka Uryu [sup.1] [...]

Background: As the COVID-19 pandemic emerged, and social distancing increased, the physical activity (PA) of people decreased, which increased depression. The purpose of this study was to analyze the relationship between self-reported changes in PA with the COVID-19 pandemic and major depression according to moderate to vigorous physical activity (MVPA) status. Methods: This study included 228,457 adults and used data from the Korea Community Health Survey 2020. Multiple logistic regression analysis was performed to evaluate the relationship between self-reported changes in PA and major depression stratified by MVPA status. Results: The percentage of participants who reported decreases in PA was 39.5% in men and 44.7% in women compared with the pre-COVID-19 pandemic period. Those who reported decreases in PA after the onset of COVID-19 had major depression (men odds ratio = 1.28; 95% confidence interval, 1.15–1.43 and women odds ratio = 1.35; 95% confidence interval, 1.25–1.46). Women who were moderately or vigorously physically active had higher odds of major depression when they reported decreases in PA (odds ratio = 1.31; 95% confidence interval, 1.06–1.62). Conclusions: People who reported decreases in PA were associated with major depression compared with the pre-COVID-19 pandemic period. Based on this, the government should encourage exercise to reduce major depression and provide guidelines for PA at home or outdoors. [ABSTRACT FROM AUTHOR]

We have investigated the degradation mechanism of solution-processed indium-gallium-zinc-oxide (IGZO) thin-film transistors. The threshold voltage shift (Δ V th ) followed a linear function under negative gate bias stress (NBS), while it showed a stretched-exponential behavior under positive gate bias stress. The slope of Δ V th for stress time was rarely changed with variations below 0.3 mV/s. The thickness of the fabricated IGZO layer (In 0.51 Ga 0.15 Zn 0.34 O) was approximately 10 nm. The Debye length ( L D ) was larger than IGZO thickness ( t IGZO ) due to the fully depleted active layer under NBS. Therefore, the degradation phenomenon under NBS was related to the adsorption at back-channel surface. The back-channel surface could be affected by the gate bias under NBS, and the molecules adsorbed at the IGZO layer were positively charged and induced extra electrons by NBS. We verified that the number of positively charged adsorbates had a proportional relationship with the Δ V th based on the two-dimensional technology computer-aided design (TCAD) simulation. Furthermore, we investigated the degradation phenomenon with the Δ V th equation regarding the adsorbates, and the result confirmed that the adsorption process could cause the linear Δ V th . We experimentally confirmed the effect of back-channel surface by comparing the Δ V th between different atmospheric conditions and L D . Consequently, the reaction at the back-channel surface should be considered to develop the metal-oxide semiconductor devices.