Epigenetic and transcriptional regulation of CCL17 production by glucocorticoids in arthritis.

Glucocorticoids (GCs) are potent anti-inflammatory agents and are broadly used in treating rheumatoid arthritis (RA) patients, albeit with adverse side effects associated with long-term usage. The negative consequences of GC therapy provide an impetus for research into gaining insights into the molecular mechanisms of GC action. We have previously reported that granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced CCL17 has a non-redundant role in inflammatory arthritis.

Active maintenance of CD8 T cell naivety through regulation of global genome architecture.

The differentiation of naive CD8 T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8 T cells.

Targeting BMI-1 to deplete antibody-secreting cells in autoimmunity.

Objectives: B cells drive the production of autoreactive antibody-secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long-term organ damage. Current treatments for antibody-mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre-existing long-lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies.

The ENCODE Uniform Analysis Pipelines.

The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the and genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community.

Chromatin alternates between A and B compartments at kilobase scale for subgenic organization.

Nuclear compartments are prominent features of 3D chromatin organization, but sequencing depth limitations have impeded investigation at ultra fine-scale. CTCF loops are generally studied at a finer scale, but the impact of looping on proximal interactions remains enigmatic. Here, we critically examine nuclear compartments and CTCF loop-proximal interactions using a combination of in situ Hi-C at unparalleled depth, algorithm development, and biophysical modeling.

The ENCODE Uniform Analysis Pipelines.

The Encyclopedia of DNA elements (ENCODE) project is a collaborative effort to create a comprehensive catalog of functional elements in the human genome. The current database comprises more than 19000 functional genomics experiments across more than 1000 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory and transcriptional landscape of the and genomes. All experimental data, metadata, and associated computational analyses created by the ENCODE consortium are submitted to the Data Coordination Center (DCC) for validation, tracking, storage, and distribution to community resources and the scientific community.

Insights from Spatial Measures of Intolerance to Identifying Pathogenic Variants in Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are a group of epilepsies with early onset and severe symptoms that sometimes lead to death. Although previous work successfully discovered several genes implicated in disease outcomes, it remains challenging to identify causative mutations within these genes from the background variation present in all individuals due to disease heterogeneity. Nevertheless, our ability to detect possible pathogenic variants has continued to improve as predictors of deleteriousness have advanced.

Active maintenance of CD8 T cell naïvety through regulation of global genome architecture.

The differentiation of naïve CD8 cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8 T cells.

SATB1 ensures appropriate transcriptional programs within naïve CD8 T cells.

Special AT-binding protein 1 (SATB1) is a chromatin-binding protein that has been shown to be a key regulator of T-cell development and CD4 T-cell fate decisions and function. The underlying function for SATB1 in peripheral CD8 T-cell differentiation processes is largely unknown. To address this, we examined SATB1-binding patterns in naïve and effector CD8 T cells demonstrating that SATB1 binds to noncoding regulatory elements linked to T-cell lineage-specific gene programs, particularly in naïve CD8 T cells.

Detection of Chimeric Cellular: HIV mRNAs Generated Through Aberrant Splicing in HIV-1 Latently Infected Resting CD4+ T Cells.

Latent HIV-1 provirus in infected individuals on suppressive therapy does not always remain transcriptionally silent. Both HIV-1 LTR and human gene promoter derived transcriptional events can contribute HIV-1 sequences to the mRNA produced in the cell. In addition, chimeric cellular:HIV mRNA can arise through readthrough transcription and aberrant splicing.

High expression of CD38 and MHC class II on CD8 T cells during severe influenza disease reflects bystander activation and trogocytosis.

Objectives: Although co-expression of CD38 and HLA-DR reflects T-cell activation during viral infections, high and prolonged CD38HLA-DR expression is associated with severe disease. To date, the mechanism underpinning expression of CD38HLA-DR is poorly understood.

Methods: We used mouse models of influenza A/H9N2, A/H7N9 and A/H3N2 infection to investigate mechanisms underpinning CD38MHC-II phenotype on CD8 T cells.

MTR3D: identifying regions within protein tertiary structures under purifying selection.

The identification of disease-causal variants is non-trivial. By mapping population variation from over 448,000 exome and genome sequences to over 81,000 experimental structures and homology models of the human proteome, we have calculated both regional intolerance to missense variation (Missense Tolerance Ratio, MTR), using a sliding window of 21-41 codons, and introduce a new 3D spatial intolerance to missense variation score (3D Missense Tolerance Ratio, MTR3D), using spheres of 5-8 Å. We show that the MTR3D is less biased by regions with limited data and more accurately identifies regions under purifying selection than estimates relying on the sequence alone.

Ptpn2 and KLRG1 regulate the generation and function of tissue-resident memory CD8+ T cells in skin.

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection.

KDM6B-dependent chromatin remodeling underpins effective virus-specific CD8 T cell differentiation.

Naive CD8 T cell activation results in an autonomous program of cellular proliferation and differentiation. However, the mechanisms that underpin this process are unclear. Here, we profile genome-wide changes in chromatin accessibility, gene transcription, and the deposition of a key chromatin modification (H3K27me3) early after naive CD8 T cell activation.

A saturating mutagenesis CRISPR-Cas9-mediated functional genomic screen identifies and regulatory elements of in murine ESCs.

Regulatory elements (REs) consist of enhancers and promoters that occupy a significant portion of the noncoding genome and control gene expression programs either in or in Putative REs have been identified largely based on their regulatory features (co-occupancy of ESC-specific transcription factors, enhancer histone marks, and DNase hypersensitivity) in mouse embryonic stem cells (mESCs). However, less has been established regarding their regulatory functions in their native context. We deployed and regulatory elements scanning through saturating mutagenesis and sequencing (ctSCAN-SMS) to target elements within the ∼12-kb -region (REs; CREs) of the gene locus, as well as genome-wide 2,613 high-confidence REs (TREs), in mESCs.

Activation and In Vivo Evolution of the MAIT Cell Transcriptome in Mice and Humans Reveals Tissue Repair Functionality.

Mucosal-associated invariant T (MAIT) cells are MR1-restricted innate-like T cells conserved across mammalian species, including mice and humans. By sequencing RNA from sorted MR1-5-OP-RU tetramer cells derived from either human blood or murine lungs, we define the basic transcriptome of an activated MAIT cell in both species and demonstrate how this profile changes during the resolution of infection and during reinfection. We observe strong similarities between MAIT cells in humans and mice.

Early T-BET Expression Ensures an Appropriate CD8 Lineage-Specific Transcriptional Landscape after Influenza A Virus Infection.

Virus infection triggers large-scale changes in the phenotype and function of naive CD8 T cells, resulting in the generation of effector and memory T cells that are then critical for immune clearance. The T-BOX family of transcription factors (TFs) are known to play a key role in T cell differentiation, with mice deficient for the TF T-BET (encoded by unable to generate optimal virus-specific effector responses. Although the importance of T-BET in directing optimal virus-specific T cell responses is accepted, the precise timing and molecular mechanism of action remains unclear.

CD4 T help promotes influenza virus-specific CD8 T cell memory by limiting metabolic dysfunction.

There is continued interest in developing novel vaccine strategies that induce establish optimal CD8 cytotoxic T lymphocyte (CTL) memory for pathogens like the influenza A viruses (IAVs), where the recall of IAV-specific T cell immunity is able to protect against serologically distinct IAV infection. While it is well established that CD4 T cell help is required for optimal CTL responses and the establishment of memory, when and how CD4 T cell help contributes to determining the ideal memory phenotype remains unclear. We assessed the quality of IAV-specific CD8 T cell memory established in the presence or absence of a concurrent CD4 T cell response.

Unique Transcriptional Architecture in Airway Epithelial Cells and Macrophages Shapes Distinct Responses following Influenza Virus Infection .

Airway epithelial cells and macrophages differ markedly in their responses to influenza A virus (IAV) infection. To investigate transcriptional responses underlying these differences, purified subsets of type II airway epithelial cells (ATII) and alveolar macrophages (AM) recovered from the lungs of mock- or IAV-infected mice at 9 h postinfection were subjected to RNA sequencing. This time point was chosen to allow for characterization of cell types first infected with the virus inoculum, prior to multicycle virus replication and the infiltration of inflammatory cells into the airways.

Glucocorticoids promote apoptosis of proinflammatory monocytes by inhibiting ERK activity.

Glucocorticoids (GCs) are potent anti-inflammatory drugs whose mode of action is complex and still debatable. One likely cellular target of GCs are monocytes/macrophages. The role of GCs in monocyte survival is also debated.

Regulation of H3K4me3 at Transcriptional Enhancers Characterizes Acquisition of Virus-Specific CD8 T Cell-Lineage-Specific Function.

Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ∼25,000 putative CD8 T cell transcriptional enhancers (TEs) differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3) chromatin signature upon differentiation.

Identification of genes differentially expressed in menstrual breakdown and repair.

Study Question: Does the changing molecular profile of the endometrium during menstruation correlate with the histological profile of menstruation.

Summary Answer: We identified several genes not previously associated with menstruation; on Day 2 of menstruation (early-menstruation), processes related to inflammation are predominantly up-regulated and on Day 4 (late-menstruation), the endometrium is predominantly repairing and regenerating.

What Is Known Already: Menstruation is induced by progesterone withdrawal at the end of the menstrual cycle and involves endometrial tissue breakdown, regeneration and repair.