Phase separation drives aberrant chromatin looping and cancer development.

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 residues1,2. 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 leukaemias1,2, 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 protein3,4, 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 diseases1,2,4-7, this mechanism can potentially be generalized to many malignant and pathological settings.

PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation.

Dysregulation of polycomb repressive complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing trimethylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19; also known as polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. Chromatin immunoprecipitation followed by sequencing profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains, possibly due to impaired H3K27me3 spreading from cytosine guanine dinucleotide islands, which is reminiscent to the reported effect of an "onco"-histone mutation, H3K27 to methionine (H3K27M). RNA-sequencing-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression. Correlation studies using patient sample data sets further support a clinical relevance of the PHF19-regulated pathways. Lastly, we show that MM cells are generally sensitive to PRC2 inhibitors. Collectively, this study demonstrates that PHF19 promotes MM tumorigenesis through enhancing H3K27me3 deposition and PRC2's gene-regulatory functions, lending support for PRC2 blockade as a means for MM therapeutics.

Understanding histone H3 lysine 36 methylation and its deregulation in disease.

Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.

Chemical composition and antimicrobial activity of the essential oil of apricot seed.

In traditional oriental medicine, apricot (Prunus armeniaca L.) seed has been used to treat skin diseases such as furuncle, acne vulgaris and dandruff, as well as coughing, asthma and constipation. This study describes the phytochemical profile and antimicrobial potential of the essential oil obtained from apricot seeds (Armeniacae Semen). The essential oil isolated by hydrodistillation was analysed by gas chromatography-mass spectroscopy. Benzaldehyde (90.6%), mandelonitrile (5.2%) and benzoic acid (4.1%) were identified. Disc diffusion, agar dilution and gaseous contact methods were performed to determine the antimicrobial activity against 16 bacteria and two yeast species. The minimum inhibitory concentrations ranged from 250 to 4000, 500 to 2000 and 250 to 1000 µg/mL for Gram-positive bacteria, Gram-negative bacteria and yeast strains, respectively. The minimum inhibitory doses by gaseous contact ranged from 12.5 to 50, 12.5 to 50 and 3.13 to 12.5 mg/L air for Gram-positive bacteria, Gram-negative bacteria and yeast strains, respectively. The essential oil exhibited a variable degree of antimicrobial activity against a range of bacteria and yeasts tested.

Do the Self-Reported Changes in Physical Activity After the Emergence of the COVID-19 Pandemic Associate With Major Depression According to Moderate to Vigorous Physical Activity Status?

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.

Gender differences in the association between multimorbidity and depression in older Korean adults: an analysis of data from the National Survey of Older Koreans (2011-2017).

OBJECTIVES: Previous studies have shown that people with multimorbidity have a higher risk of depression than those without multimorbidity. However, few studies have examined the association between depression and multimorbidity in men and women separately. Since the rates of depression and multimorbidity are different in men and women, it is necessary to examine whether gender differences affect their association. METHODS: This study included 30,138 participants (aged ≥ 65 years) from the National Survey of Older Koreans (2011-2017). Depression was defined using the Korean version of the Geriatric Depression Scale (SGDS-K). Multimorbidity was defined as people who had 2 or more chronic diseases, including arthritis, diabetes, heart disease, hypertension, pulmonary disease, cancer, stroke, or osteoporosis. Multiple logistic regression analysis was performed to determine the association between depression and multimorbidity. RESULTS: In total, 22.2% and 30.7% of men and women, respectively, had depression. Those with multimorbidity had a higher risk of depression than those without chronic conditions; specifically, the difference in risk among men was greater than that among women. Age was considered a moderator for women. While the effects of pulmonary disease, stroke, and cancer were especially substantial in the integrated analysis, gender differences were observed related to various chronic conditions comorbid with heart disease. CONCLUSIONS: There are gender differences in the association between multimorbidity and depression among older Korean adults. Therefore, gender-specific care should be provided to reduce depression in older adults with multimorbidity.

Effect of Back-Channel Surface on Reliability of Solution-Processed In0.51Ga0.15Zn0.34O Thin-Film Transistors with Thin Active Layer.

We have investigated the degradation mechanism of solution-processed indium-gallium-zinc-oxide (IGZO) thin-film transistors. The threshold voltage shift (ΔVth) 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 ΔVth for stress time was rarely changed with variations below 0.3 mV/s. The thickness of the fabricated IGZO layer (In0.51Ga0.15Zn0.34O) was approximately 10 nm. The Debye length (LD) was larger than IGZO thickness (tIGZO) 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 ΔVth based on the two-dimensional technology computer-aided design (TCAD) simulation. Furthermore, we investigated the degradation phenomenon with the ΔVth equation regarding the adsorbates, and the result confirmed that the adsorption process could cause the linear ΔVth. We experimentally confirmed the effect of back-channel surface by comparing the ΔVth between different atmospheric conditions and LD. Consequently, the reaction at the back-channel surface should be considered to develop the metal-oxide semiconductor devices.

Oncogenic fusion proteins and their role in three-dimensional chromatin structure, phase separation, and cancer.

Three-dimensional (3D) chromatin structure plays a critical role in development, gene regulation, and cellular identity. Alterations to this structure can have profound effects on cellular phenotypes and have been associated with a variety of diseases including multiple types of cancer. One of several forces that help shape 3D chromatin structure is liquid-liquid phase separation, a form of self-association between biomolecules that can sequester regions of chromatin into subnuclear droplets or even membraneless organelles like nucleoli. This review focuses on a class of oncogenic fusion proteins that appear to exert their oncogenic function via phase-separation-driven alterations to 3D chromatin structure. Here, we review what is known about the mechanisms by which these oncogenic fusion proteins phase separate in the nucleus and their role in shaping the 3D chromatin structure. We discuss the potential for this phenomenon to be a more widespread mechanism of oncogenesis.

ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism.

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-'reading' bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

BAHCC1 binds H3K27me3 via a conserved BAH module to mediate gene silencing and oncogenesis.

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'.