Dynamic landscape of immune cell-specific gene regulation in immune-mediated diseases

Abstract The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

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Single-cell biology to decode the immune cellular composition of kidney inflammation

Cell and Tissue Research ◽

10.1007/s00441-021-03483-y ◽

2021 ◽

Author(s):

Yu Zhao ◽

Ulf Panzer ◽

Stefan Bonn ◽

Christian F. Krebs

Keyword(s):

Single Cell ◽

Cell Biology ◽

Computational Analysis ◽

Immune Cell ◽

Therapeutic Interventions ◽

Experimental Setup ◽

Disease Etiology ◽

Rna Profiling ◽

Immune Mediated ◽

Health And Disease

AbstractSingle-cell biology is transforming the ability of researchers to understand cellular signaling and identity across medical and biological disciplines. Especially for immune-mediated diseases, a single-cell look at immune cell subtypes, signaling, and activity might yield fundamental insights into the disease etiology, mechanisms, and potential therapeutic interventions. In this review, we highlight recent advances in the field of single-cell RNA profiling and their application to understand renal function in health and disease. With a focus on the immune system, in particular on T cells, we propose some key directions of understanding renal inflammation using single-cell approaches. We detail the benefits and shortcomings of the various technological approaches outlined and give advice on potential pitfalls and challenges in experimental setup and computational analysis. Finally, we conclude with a brief outlook into a promising future for single-cell technologies to elucidate kidney function.

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SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms

Scientific Reports ◽

10.1038/s41598-021-80999-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ye Wang ◽

Morvarid Mohseni ◽

Angelo Grauel ◽

Javier Estrada Diez ◽

Wei Guan ◽

...

Keyword(s):

T Cell ◽

Tumor Immunity ◽

Immune Cell ◽

Tumor Regression ◽

Tyrosine Phosphatase ◽

Cytotoxic T Cell ◽

Cell Recruitment ◽

Inhibitory Function ◽

Immune Mediated ◽

Cytotoxic Function

AbstractSHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

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The Intersection of Metformin and Inflammation

AJP Cell Physiology ◽

10.1152/ajpcell.00604.2020 ◽

2021 ◽

Author(s):

Leena P. Bharath ◽

Barbara S. Nikolajczyk

Keyword(s):

Mitochondrial Function ◽

Immune Cells ◽

Immune Cell ◽

Cell Types ◽

Remarkable Effect ◽

Tumor Onset ◽

Age Related ◽

Immune Mediated ◽

Autoimmune Conditions ◽

Near Term

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy, is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. Here we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

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Identification of MEF2-regulated genes during muscle differentiation

Physiological Genomics ◽

10.1152/physiolgenomics.00149.2004 ◽

2004 ◽

Vol 20 (1) ◽

pp. 143-151 ◽

Cited By ~ 19

Author(s):

James Paris ◽

Carl Virtanen ◽

Zhibin Lu ◽

Mark Takahashi

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Transcription Factors ◽

Neuromuscular Junctions ◽

Muscle Differentiation ◽

Signaling Cascades ◽

Specific Gene ◽

Genetic Mechanisms ◽

Selection Parameters ◽

First Time

Although a great deal has been elucidated concerning the mechanisms regulating muscle differentiation, little is known about transcription factor-specific gene regulation. Our understanding of the genetic mechanisms regulating cell differentiation is quite limited. Much of what has been defined centers on regulatory signaling cascades and transcription factors. Surprisingly few studies have investigated the association of genes with specific transcription factors. To address these issues, we have utilized a method coupling chromatin immunoprecipitation and CpG microarrays to characterize the genes associated with MEF2 in differentiating C2C12 cells. Results demonstrated a defined binding pattern over the course of differentiation. Filtered data demonstrated 9 clones to be elevated at 0 h, 792 at 6 h, 163 by 1 day, and 316 at 3 days. Using unbiased selection parameters, we selected a subset of 291 prospective candidates. Clones were sequenced and filtered for removal of redundancy between clones and for the presence of repetitive elements. We were able to place 50 of these on the mouse genome, and 20 were found to be located near well-annotated genes. From this list, previously undefined associations with MEF2 were discovered. Many of these genes represent proteins involved in neurogenesis, neuromuscular junctions, signaling and metabolism. The remaining clones include many full-length cDNA and represent novel gene targets. The results of this study provides for the first time, a unique look at gene regulation at the level of transcription factor binding in differentiating muscle.

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Hand2 Affects Neurogenesis and Cell Type-specific Gene Regulation in Neural Crest-derived Precursors of Autonomic Neurons

Microscopy and Microanalysis ◽

10.1017/s1431927607071139 ◽

2007 ◽

Vol 13 (S02) ◽

Author(s):

M Howard

Keyword(s):

Gene Regulation ◽

Neural Crest ◽

Specific Gene ◽

Cell Type ◽

Autonomic Neurons ◽

Cell Type Specific

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Tuning cancer fate: the unremitting role of host immunity

Open Biology ◽

10.1098/rsob.170006 ◽

2017 ◽

Vol 7 (4) ◽

pp. 170006 ◽

Cited By ~ 22

Author(s):

B. Calì ◽

B. Molon ◽

A. Viola

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Tumour Progression ◽

Host Immunity ◽

Adaptive Immune ◽

Adaptive Immune Cells ◽

Immune Mediated ◽

Immune Cell Subsets ◽

Therapeutic Protocols

Host immunity plays a central and complex role in dictating tumour progression. Solid tumours are commonly infiltrated by a large number of immune cells that dynamically interact with the surrounding microenvironment. At first, innate and adaptive immune cells successfully cooperate to eradicate microcolonies of transformed cells. Concomitantly, surviving tumour clones start to proliferate and harness immune responses by specifically hijacking anti-tumour effector mechanisms and fostering the accumulation of immunosuppressive immune cell subsets at the tumour site. This pliable interplay between immune and malignant cells is a relentless process that has been concisely organized in three different phases: elimination, equilibrium and escape. In this review, we aim to depict the distinct immune cell subsets and immune-mediated responses characterizing the tumour landscape throughout the three interconnected phases. Importantly, the identification of key immune players and molecules involved in the dynamic crosstalk between tumour and immune system has been crucial for the introduction of reliable prognostic factors and effective therapeutic protocols against cancers.

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FIREcaller: Detecting Frequently Interacting Regions from Hi-C Data

10.1101/619288 ◽

2019 ◽

Cited By ~ 3

Author(s):

Cheynna Crowley ◽

Yuchen Yang ◽

Yunjiang Qiu ◽

Benxia Hu ◽

Armen Abnousi ◽

...

Keyword(s):

Gene Regulation ◽

Spatial Organization ◽

R Package ◽

Specific Gene ◽

List Type ◽

Cell Type ◽

R Software ◽

Computational Tools ◽

Cell Type Specific ◽

User Friendly

AbstractHi-C experiments have been widely adopted to study chromatin spatial organization, which plays an essential role in genome function. We have recently identified frequently interacting regions (FIREs) and found that they are closely associated with cell-type-specific gene regulation. However, computational tools for detecting FIREs from Hi-C data are still lacking. In this work, we present FIREcaller, a stand-alone, user-friendly R package for detecting FIREs from Hi-C data. FIREcaller takes raw Hi-C contact matrices as input, performs within-sample and cross-sample normalization, and outputs continuous FIRE scores, dichotomous FIREs, and super-FIREs. Applying FIREcaller to Hi-C data from various human tissues, we demonstrate that FIREs and super-FIREs identified, in a tissue-specific manner, are closely related to gene regulation, are enriched for enhancer-promoter (E-P) interactions, tend to overlap with regions exhibiting epigenomic signatures of cis-regulatory roles, and aid the interpretation or GWAS variants. The FIREcaller package is implemented in R and freely available at https://yunliweb.its.unc.edu/FIREcaller.Highlights– Frequently Interacting Regions (FIREs) can be used to identify tissue and cell-type-specific cis-regulatory regions.– An R software, FIREcaller, has been developed to identify FIREs and clustered FIREs into super-FIREs.

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