Faculty Opinions recommendation of Allele-specific chromatin remodeling in the ZPBP2/GSDMB/ORMDL3 locus associated with the risk of asthma and autoimmune disease.

Genome-wide association studies have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variant(s) within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.

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Allele-specific chromatin remodeling of the tumor necrosis factor-α promoter

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2006.10.114 ◽

2006 ◽

Vol 351 (3) ◽

pp. 777-783 ◽

Cited By ~ 14

Author(s):

Tiina Skoog ◽

Anders Hamsten ◽

Per Eriksson

Keyword(s):

Tumor Necrosis Factor ◽

Chromatin Remodeling ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Allele Specific ◽

Factor Α ◽

Necrosis Factor

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HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization

Scientific Reports ◽

10.1038/s41598-021-82195-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Vincent van Drongelen ◽

Bruna Miglioranza Scavuzzi ◽

Sarah Veloso Nogueira ◽

Frederick W. Miller ◽

Amr H. Sawalha ◽

...

Keyword(s):

Autoimmune Disease ◽

Immune Modulation ◽

Disease Risk ◽

Macrophage Polarization ◽

Specific Antigen ◽

Human Leukocyte ◽

Allele Specific ◽

Anti Inflammatory ◽

Mechanistic Basis

AbstractAssociations between particular human leukocyte antigen (HLA) alleles and susceptibility to—or protection from—autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory (“M1”) versus anti-inflammatory (“M2”) macrophages, respectively. RNA-sequencing analyses of in vitro-polarized macrophages in the presence of AP-incompetent short synthetic peptides corresponding to the third allelic hypervariable regions coded by those two HLA-DRB1 alleles showed reciprocal activation of pro- versus anti-inflammatory transcriptomes, with implication of corresponding gene ontologies and upstream regulators. These results identify a previously unrecognized mechanism of differential immune modulation by short HLA-DRB1-coded allelic epitopes independent of AP, and could shed new light on the mechanistic basis of HLA-disease association.

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13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking

Blood ◽

10.1182/blood.2019004684 ◽

2020 ◽

Vol 136 (8) ◽

pp. 946-956 ◽

Cited By ~ 2

Author(s):

Minjun Yang ◽

Setareh Safavi ◽

Eleanor L. Woodward ◽

Nicolas Duployez ◽

Linda Olsson-Arvidsson ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Chromatin Remodeling ◽

Lymphoblastic Leukemia ◽

Driver Gene ◽

Phosphatidylinositol 3 Kinase ◽

Cell Precursor ◽

Downstream Signaling ◽

Allele Specific ◽

Flt3 Expression

Abstract Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5′ of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.

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Antigen Presentation-Independent Reciprocal Immune Modulation by HLA-DRB1 Allelic Epitopes that Associate with Autoimmune Disease Risk or Protection

10.1101/2020.08.25.265348 ◽

2020 ◽

Author(s):

Vincent van Drongelen ◽

Bruna Miglioranza Scavuzzi ◽

Sarah Veloso Nogueira ◽

Frederick W. Miller ◽

Amr H. Sawalha ◽

...

Keyword(s):

Autoimmune Disease ◽

Antigen Presentation ◽

Immune Modulation ◽

Disease Risk ◽

Specific Antigen ◽

Human Leukocyte ◽

Allele Specific ◽

Anti Inflammatory ◽

Mechanistic Basis

AbstractStatistical associations between particular human leukocyte antigen (HLA) alleles and susceptibility to - or protection from - autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit mechanism; however, direct evidence to substantiate that hypothesis is scant. Here we demonstrate AP-independent differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory (“M1”) versus anti-inflammatory (“M2”) macrophages, respectively. RNA-sequencing analyses of in vitro-polarized macrophages in the presence of AP-incompetent short synthetic peptides corresponding to the third allelic hypervariable regions coded by those two HLA-DRB1 alleles showed reciprocal activation of pro- versus anti-inflammatory transcriptomes, with implication of corresponding gene ontologies and upstream regulators. These results identify a previously unrecognized mechanism of differential immune modulation by short HLA-DRB1-coded allelic epitopes independent of AP, and could shed new light on the mechanistic basis of HLA-disease association.

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Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer

10.1101/2020.10.23.349407 ◽

2020 ◽

Author(s):

Chi-Yun Wu ◽

Billy T. Lau ◽

Heonseok Kim ◽

Anuja Sathe ◽

Susan M. Grimes ◽

...

Keyword(s):

Single Cell ◽

Chromatin Remodeling ◽

Copy Number ◽

Gastric Cancer Cell Line ◽

Chromatin Accessibility ◽

Intratumor Heterogeneity ◽

Tumor Evolution ◽

Copy Number Aberrations ◽

Allele Specific ◽

Allelic Copy Number

AbstractCancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.

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Alleloscope: Integrative single cell analysis of allele-specific copy number alterations and chromatin accessibility in cancer

10.21203/rs.3.rs-98536/v1 ◽

2020 ◽

Author(s):

Chi-Yun Wu ◽

Billy Lau ◽

Heonseok Kim ◽

Anuja Sathe ◽

Susan M Grimes ◽

...

Keyword(s):

Single Cell ◽

Chromatin Remodeling ◽

Copy Number ◽

Gastric Cancer Cell Line ◽

Chromatin Accessibility ◽

Intratumor Heterogeneity ◽

Tumor Evolution ◽

Copy Number Aberrations ◽

Allele Specific ◽

Allelic Copy Number

Abstract Cancer progression is driven by both somatic copy number aberrations (CNAs) and chromatin remodeling, yet little is known about the interplay between these two classes of events in shaping the clonal diversity of cancers. We present Alleloscope, a method for allele-specific copy number estimation that can be applied to single cell DNA and ATAC sequencing data, either separately or in combination. This approach allows for integrative multi-omic analysis of allele-specific copy number and chromatin accessibility on the same cell. On scDNA-seq data from gastric, colorectal, and breast cancer samples, with extensive validation using matched linked-read sequencing, Alleloscope finds pervasive occurrence of highly complex, multi-allelic copy number aberrations, where cells that carry varying allelic configurations adding to the same total copy number co-evolve within a tumor. The contributions of such allele-specific events to intratumor heterogeneity have been under-reported and under-studied due to the lack of methods for their detection. On scATAC-seq from two basal cell carcinoma samples and a gastric cancer cell line, Alleloscope detects multi-allelic copy number events and copy neutral loss-of-heterozygosity, enabling the dissection of the contributions of chromosomal instability and chromatin remodeling in tumor evolution.

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Role of DNA Methylation and Histone H3 Lysine 27 Methylation in Tissue-Specific Imprinting of Mouse Grb10

Molecular and Cellular Biology ◽

10.1128/mcb.01329-06 ◽

2006 ◽

Vol 27 (2) ◽

pp. 732-742 ◽

Cited By ~ 37

Author(s):

Yoko Yamasaki-Ishizaki ◽

Tomohiko Kayashima ◽

Christophe K. Mapendano ◽

Hidenobu Soejima ◽

Tohru Ohta ◽

...

Keyword(s):

Dna Methylation ◽

Chromatin Remodeling ◽

Histone H3 ◽

Paternal Allele ◽

Major Type ◽

Pcr Analysis ◽

Specific Expression ◽

Tissue Specific ◽

Allele Specific ◽

The Brain

ABSTRACT Mouse Grb10 is a tissue-specific imprinted gene with promoter-specific expression. In most tissues, Grb10 is expressed exclusively from the major-type promoter of the maternal allele, whereas in the brain, it is expressed predominantly from the brain type promoter of the paternal allele. Such reciprocally imprinted expression in the brain and other tissues is thought to be regulated by DNA methylation and the Polycomb group (PcG) protein Eed. To investigate how DNA methylation and chromatin remodeling by PcG proteins coordinate tissue-specific imprinting of Grb10, we analyzed epigenetic modifications associated with Grb10 expression in cultured brain cells. Reverse transcriptase PCR analysis revealed that the imprinted paternal expression of Grb10 in the brain implied neuron-specific and developmental stage-specific expression from the paternal brain type promoter, whereas in glial cells and fibroblasts, Grb10 was reciprocally expressed from the maternal major-type promoter. The cell-specific imprinted expression was not directly related to allele-specific DNA methylation in the promoters because the major-type promoter remained biallelically hypomethylated regardless of its activity, whereas gametic DNA methylation in the brain type promoter was maintained during differentiation. Histone modification analysis showed that allelic methylation of histone H3 lysine 4 and H3 lysine 9 were associated with gametic DNA methylation in the brain type promoter, whereas that of H3 lysine 27 regulated by the Eed PcG complex was detected in the paternal major-type promoter, corresponding to its allele-specific silencing. Here, we propose a molecular model that gametic DNA methylation and chromatin remodeling by PcG proteins during cell differentiation cause tissue-specific imprinting in embryonic tissues.

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Laryngeal Manifestations of Autoimmune Diseases

Perspectives of the ASHA Special Interest Groups ◽

10.1044/2020_persp-19-00168 ◽

2020 ◽

Vol 5 (2) ◽

pp. 439-456

Author(s):

Jenny L. Pierce

Keyword(s):

Autoimmune Disease ◽

Autoimmune Diseases ◽

Patient Outcomes ◽

Correct Diagnosis ◽

Upper Airway ◽

Clinical Implications ◽

Laryngeal Function ◽

The Past ◽

Referral Practices ◽

Timely Referral

Purpose This review article provides an overview of autoimmune diseases and their effects on voice and laryngeal function. Method A literature review was conducted in PubMed. Combinations of the following keywords were used: “autoimmune disease and upper airway,” “larynx,” “cough,” “voice,” “dysphonia,” and “dyspnea.” Precedence was given to articles published in the past 10 years due to recent advances in this area and to review articles. Ultimately, 115 articles were included for review. Results Approximately 81 autoimmune diseases exist, with 18 of those highlighted in the literature as having laryngeal involvement. The general and laryngeal manifestations of these 18 are discussed in detail, in addition to the clinical implications for a laryngeal expert. Conclusions Voice, breathing, and cough symptoms may be an indication of underlying autoimmune disease. However, these symptoms are often similar to those in the general population. Appropriate differential diagnosis and timely referral practices maximize patient outcomes. Guidelines are provided to facilitate correct diagnosis when an autoimmune disease is suspected.

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