Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input “easy Hi-C” protocol to map the 3D genome ...architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.
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•HiCorr allows robust mapping of sub-TAD chromatin interactions with Hi-C•Low-input “easy Hi-C” protocol compatible with 50–100k cells•Enhancer loops and aggregates are better marks of cell identity than compartments•Chromatin loops outperform eQTLs in defining neurological GWAS target genes
Lu et al. developed a rigorous Hi-C bias-correction pipeline to significantly improve the robustness of high-resolution chromatin interaction maps. With a new low-input “easy Hi-C” protocol, they mapped chromatin interactions in neural samples, defined cell-type-specific enhancer loops and aggregates, and concluded that Hi-C outperforms eQTL in explaining GWAS results.
Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using ...single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone
. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.
The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. ...Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.
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•EZH2 and BCL6 mediate combinatorial tethering of non-canonical PRC1-BCOR complex•CBX8 binding to bivalent promoters enables GC B cell-specific PRC1-BCOR recruitment•BCOR tethering by EZH2 activity and BCL6 is required for GC and drives GC hyperplasia•Combinatorial targeting of EZH2 and BCL6 yields enhanced anti-lymphoma effect
Béguelin et al. show that EZH2 and BCL6 cooperate to recruit a non-canonical PRC1/BCOR complex containing CBX8 to repress differentiation gene expression in germinal center B cells and promote lymphomagenesis. Targeting both BCL6 and EZH2 elicits strong anti-lymphoma activity in diffuse large B cell lymphoma.
The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic ...inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
•EZH2 is required for germinal center formation and immunoglobulin affinity maturation•Conditional expression of an EZH2 mutant lymphoma allele drives GC hyperplasia in vivo•Mutant EZH2 functions in part through aberrant repression of GC-specific bivalent promoters•EZH2 cooperates with BCL2 to initiate and maintain diffuse large B cell lymphomas
Abstract
Institutionalized gangs are youth groups that have developed the ability to persist, expand, and restructure organizationally around criminal activities and have imposed their norms and ...behavioral prescriptions on the communities where they operate. So how does a gang member manage to leave these groups and abandon violent crime? This article proposes a new theoretical model of gang disengagement based on a comparative case study with MS‐13 and Barrio 18 gangs in Central America. It is based on 112 in‐depth interviews with former gang members in El Salvador, Guatemala, and Honduras. The article identifies three forms of gang disengagement: religious conversion, secular pass, and walking away. Two factors, the gang's organizational structure and its territorial reach, mediate in the choices gang members have when leaving an institutionalized gang. The specific combination of these factors makes some disengagement modes more likely than others. The article underscores the role of gang governance in shaping gang members’ disengagement processes.
Abstract
Is it possible to disengage from street gangs in communities and districts where gang organizations rule? We argue that disengagement is possible when this process does not alter the social ...order that allows street gangs to continue controlling and establishing the rules that govern economic activities and relationships in the barrios they control. We explore the process of gang disengagement under criminal governance in El Salvador, a country plagued by the powerful MS-13 and Barrio 18 gangs. We conducted a survey with nearly 1,200 people with a history of gang membership and 25 in-depth interviews with former gang members. We find that disengagement through religious conversion allows the gang to continue exerting power over the deserters, while at the same time enforcing religious commitment to the congregation. The religious community provides the normative framework that reassures the gang that its former associates will not act against it, consolidating its local authority.
Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. ...We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, "Variant Explorer Pipeline" (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0%), including variants in known disease-causing genes (n = 6) or candidate genes (n = 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.
Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated ...with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.
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•Neoadjuvant ICB induces local and systemic T cell responses in oral cancer patients•Treatment-responsive T cell clones recognize self-antigens including tumor antigens•Responding T cells in tumors display a tissue-resident memory program•Circulating PD-1+KLRG1-CD8 T cell frequency correlates with pathological response
Analysis of immune cell kinetics in oral cancer patients responding to neoadjuvant immune checkpoint blockade identifies diverse features in circulating and tumor-infiltrating T cell subpopulations that underlie rapid response to therapy and correlate with pathological outcome.
This article examines tough‐on‐crime strategies in El Salvador, Honduras, and Mexico. These three countries have been plagued by gangs and organized crime‐related violence. Scholars have written ...about the consequences of iron fist strategies, which have resulted in increasing levels of violence. This article seeks to fill a gap in the scholarly literature by examining what factors influence perceptions about tough‐on‐crime strategies, using survey data in the cases of Mexico, El Salvador, and Honduras. The article finds that fear is a key factor that influences support for mano dura policies.
Este artículo examina las estrategias de mano dura en El Salvador, Honduras y México. Estos tres países han estado plagados de pandillas y violencia relacionada con el crimen organizado. Los académicos han escrito sobre las consecuencias de las estrategias de mano dura, que han resultado en altos índices de violencia. Este artículo intenta llenar un vacío en la literatura académica al examinar los factores que influyen en las percepciones sobre las estrategias de mano dura, utilizando datos de encuestas en los casos de México, El Salvador y Honduras. El artículo demuestra que el miedo es un factor clave que influye en el apoyo a las políticas de mano dura.
本文分析了萨尔瓦多、洪都拉斯和墨西哥的严厉打击犯罪战略。长期以来, 这三国受到犯罪集团和有组织犯罪暴力的困扰。学者已研究了铁拳战略的结果, 该战略已导致更高程度的暴力。本文使用墨西哥、萨尔瓦多和洪都拉斯的调查数据, 分析哪些因素会影响对严厉打击犯罪战略的感知, 进而填补学术文献空白。本文发现, 恐惧是影响“对铁拳 (mano dura) 政策的支持”的一个关键因素。
There are many scholarly works focusing on organized crime and violence in Latin America. Scholars have shown empirically that tough on crime strategies have had collateral damages and have not been ...effective. By conducting logistic regression models using individual country survey data, this work seeks to analyze why tough on crime policies remain popular in some Latin American countries despite the decades of research criticizing these strategies. This article explores the cases of Colombia and Brazil, which have long histories of gang activity, organized crime, and violence. These countries also have elected presidential candidates who campaigned on iron fist strategies.
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