RNA Polymerase II coordinates histone deacetylation at active promoters.

Nucleosomes at actively transcribed promoters have specific histone post-transcriptional modifications and histone variants. These features are thought to contribute to the formation and maintenance of a permissive chromatin environment. Recent reports have drawn conflicting conclusions about whether these histone modifications depend on transcription.

Unlocking cellular plasticity: enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation from a fibroblast mesenchymal cell state to an epithelial-like state is critical for induced pluripotent stem cell (iPSC) reprogramming. In this report, we describe studies with PFI-3, a small-molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunits of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings reveal that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition during iPSC formation.

Proteasome Inhibition Reprograms Chromatin Landscape in Breast Cancer.

Unlabelled: The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear.

BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates.

Cell fate decisions are achieved with gene expression changes driven by lineage-specific transcription factors (TFs). These TFs depend on chromatin remodelers including the Brahma-related gene 1 (BRG1)-associated factor (BAF) complex to activate target genes. BAF complex subunits are essential for development and frequently mutated in cancer.

Machine learning-based morphological quantification of replicative senescence in human fibroblasts.

Although aging has been investigated extensively at the organismal and cellular level, the morphological changes that individual cells undergo along their replicative lifespan have not been precisely quantified. Here, we present the results of a readily accessible machine learning-based pipeline that uses standard fluorescence microscope and open access software to quantify the minute morphological changes that human fibroblasts undergo during their replicative lifespan in culture. Applying this pipeline in a widely used fibroblast cell line (IMR-90), we find that advanced replicative age robustly increases (+28-79%) cell surface area, perimeter, number and total length of pseudopodia, and nuclear surface area, while decreasing cell circularity, with phenotypic changes largely occurring as replicative senescence is reached.

Proteasome inhibition reprograms chromatin landscape in breast cancer.

Unlabelled: The 26S proteasome is the major protein degradation machinery in cells. Cancer cells use the proteasome to modulate gene expression networks that promote tumor growth. Proteasome inhibitors have emerged as effective cancer therapeutics, but how they work mechanistically remains unclear.

Unlocking cellular plasticity: Enhancing human iPSC reprogramming through bromodomain inhibition and extracellular matrix gene expression regulation.

The transformation of fibroblasts into epithelial cells is critical for iPSC reprogramming. In this report, we describe studies with PFI-3, a small molecule inhibitor that specifically targets the bromodomains of SMARCA2/4 and PBRM1 subunit of SWI/SNF complex, as an enhancer of iPSC reprogramming efficiency. Our findings revealed that PFI-3 induces cellular plasticity in multiple human dermal fibroblasts, leading to a mesenchymal-epithelial transition (MET) during iPSC formation.

BRG1 HSA domain interactions with BCL7 proteins are critical for remodeling and gene expression.

The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression; however, aberrant remodeling can result in cancer. We identified BCL7 proteins as critical SWI/SNF members that drive BRG1-dependent gene expression changes.

Milmed Yeast Alters the LPS-Induced M1 Microglia Cells to Form M2 Anti-Inflammatory Phenotype.

Microglial cells polarized towards a proinflammatory phenotype are considered the main cellular players of neuroinflammation, underlying several neurodegenerative diseases. Many studies have suggested that imbalance of the gut microbial composition is associated with an increase in the pro-inflammatory cytokines and oxidative stress that underlie chronic neuroinflammatory diseases, and perturbations to the gut microbiota were detected in neurodegenerative conditions such as Parkinson's disease and Alzheimer's disease. The importance of gut-brain axis has been uncovered and the relevance of an appropriate microbiota balance has been highlighted.

Visualization, benchmarking and characterization of nested single-cell heterogeneity as dynamic forest mixtures.

A major topic of debate in developmental biology centers on whether development is continuous, discontinuous, or a mixture of both. Pseudo-time trajectory models, optimal for visualizing cellular progression, model cell transitions as continuous state manifolds and do not explicitly model real-time, complex, heterogeneous systems and are challenging for benchmarking with temporal models. We present a data-driven framework that addresses these limitations with temporal single-cell data collected at discrete time points as inputs and a mixture of dependent minimum spanning trees (MSTs) as outputs, denoted as dynamic spanning forest mixtures (DSFMix).

Affirming NIH's commitment to addressing structural racism in the biomedical research enterprise.

NIH has acknowledged and committed to ending structural racism. The framework for NIH's approach, summarized here, includes understanding barriers; developing robust health disparities/equity research; improving its internal culture; being transparent and accountable; and changing the extramural ecosystem so that diversity, equity, and inclusion are reflected in funded research and the biomedical workforce.

BAF Complexes and the Glucocorticoid Receptor in Breast Cancers.

Breast cancers are a diverse group of diseases and are often characterized by their expression of receptors for hormones such as estrogen and progesterone. Recently another steroid hormone receptor, the glucocorticoid receptor (GR) has been shown to be a key player in breast cancer progression, metastasis, and treatment. These receptors bind to chromatin to elicit transcriptional changes within cells, which are often inhibited by the structure of chromatin itself.

Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes.

Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast-iPSC pairs with consistent variation in reprogramming efficiency.

Expression of UDP Glucuronosyltransferases and is associated with methylation status in prostate cancer cells.

Studies have suggested that abrogated expression of detoxification enzymes, UGT2B15 and UGT2B17, are associated with prostate tumour risk and progression. We investigated the role of EGF on the expression of these enzymes since it interacts with signalling pathways to also affect prostate tumour progression and is additionally associated with decreased DNA methylation. The expression of , methyltransferases, and was assessed in prostate cancer cells (LNCaP) treated with EGF, an EGFR inhibitor PD16893, and the methyltransferase inhibitor, 5-azacytidine, respectively.

Single-cell RNA sequencing reveals a heterogeneous response to Glucocorticoids in breast cancer cells.

Steroid hormone receptors such as the Glucocorticoid Receptor (GR) mediate transcriptional responses to hormones and are frequently targeted in the treatment of human diseases. Experiments using bulk populations of cells have provided a detailed picture of the global transcriptional hormone response but are unable to interrogate cell-to-cell transcriptional heterogeneity. To examine the glucocorticoid response in individual cells, we performed single cell RNA sequencing (scRNAseq) in a human breast cancer cell line.

Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity.

Proteasome activity is required for diverse cellular processes, including transcriptional and epigenetic regulation. However, inhibiting proteasome activity can lead to an increase in transcriptional output that is correlated with enriched levels of trimethyl H3K4 and phosphorylated forms of RNA polymerase (Pol) II at the promoter and gene body. Here, we perform gene expression analysis and ChIP followed by sequencing (ChIP-seq) in MCF-7 breast cancer cells treated with the proteasome inhibitor MG132, and we further explore genome-wide effects of proteasome inhibition on the chromatin state and RNA Pol II transcription.

Tumor suppressor SMARCB1 suppresses super-enhancers to govern hESC lineage determination.

The SWI/SNF complex is a critical regulator of pluripotency in human embryonic stem cells (hESCs), and individual subunits have varied and specific roles during development and in diseases. The core subunit SMARCB1 is required for early embryonic survival, and mutations can give rise to atypical teratoid/rhabdoid tumors (AT/RTs) in the pediatric central nervous system. We report that in contrast to other studied systems, SMARCB1 represses bivalent genes in hESCs and antagonizes chromatin accessibility at super-enhancers.

Epigenetic Enzymes, Age, and Ancestry Regulate the Efficiency of Human iPSC Reprogramming.

Epigenetic enzymes regulate higher-order chromatin architecture and cell-type specific gene expression. The ATPase BRG1 and the SWI/SNF chromatin remodeling complex are epigenetic enzymes that regulate chromatin accessibility during steady and transitional cell states. Experiments in mice show that the loss of BRG1 inhibits cellular reprogramming, while studies using human cells demonstrate that the overexpression of BRG1 enhances reprogramming.

BRG1 governs glucocorticoid receptor interactions with chromatin and pioneer factors across the genome.

The Glucocorticoid Receptor (GR) alters transcriptional activity in response to hormones by interacting with chromatin at GR binding sites (GBSs) throughout the genome. Our work in human breast cancer cells identifies three classes of GBSs with distinct epigenetic characteristics and reveals that BRG1 interacts with GBSs prior to hormone exposure. The GBSs pre-occupied by BRG1 are more accessible and transcriptionally active than other GBSs.

A dark past, a restrained present, and an apocalyptic future: time perspective, personality, and life satisfaction among anorexia nervosa patients.

Background: Despite reporting low levels of well-being, anorexia nervosa patients express temperament traits (e.g., extraversion and persistence) necessary for high levels of life satisfaction.

A role for BRG1 in the regulation of genes required for development of the lymphatic system.

Lymphatic vasculature is an important part of the cardiovascular system with multiple functions, including regulation of the return of interstitial fluid (lymph) to the bloodstream, immune responses, and fat absorption. Consequently, lymphatic vasculature defects are involved in many pathological processes, including tumor metastasis and lymphedema. BRG1 is an important player in the developmental window when the lymphatic system is initiated.