Juan I. Fuxman Bass

Boston University

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Albertha J.M. Walhout

University of Massachusetts Chan Medical School

Clarissa Stephanie Santoso

Boston University

Anna Berenson

Boston University

Jared Allan Sewell

Boston University

Zhaorong Li

Harvard University

Matthew T. Weirauch

Cincinnati Children's Hospital Medical Center

John Reece-Hoyes

Novartis (United States)

Sebastian Carrasco Pro

Tempus Labs (United States)

Samuel A. Lambert

British Heart Foundation

Timothy R. Hughes

University of Toronto

Cooperative Institutions

Harvard University

Boston University

Dana-Farber Cancer Institute

University of Buenos Aires

Consejo Nacional de Investigaciones Científicas y Técnicas

Academia Nacional de Medicina

Brigham and Women's Hospital

Boston VA Research Institute

Massachusetts Institute of Technology

University of Toronto

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Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function

Nature Immunology (2021)

Jayati Basu Bernardo Sgarbi Reis Suraj Peri Jikun Zha Hua Xiang

10.1038/s41590-021-00980-8

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Citations (15)

Figure 9—source data 1.

Kamesh Narasimhan Samuel A. Lambert Ally Wh Yang Jeremy Riddell Sanie Mnaimneh

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Intragenic proviral elements support transcription of defective HIV-1 proviruses

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Jeffrey Kuniholm Elise Armstrong Brandy Bernabe Carolyn Coote Anna Berenson

ABSTRACT HIV-establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription digital drop PCR identified Env and Nef transcripts which lacked 5’ untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5’UTR-deficient Env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo . Using 5’ rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH. Author Summary People living with HIV establish a persistent reservoir which includes latently infected cells that fuel viral rebound upon treatment interruption. However, the majority of HIV-1 genomes in these persistently infected cells are defective. Whether these defective HIV genomes are expressed and whether they contribute to HIV associated diseases including accelerated aging, neurodegenerative symptoms, and cardiovascular diseases are still outstanding questions. In this paper, we demonstrate that acute infection of macrophages and resting T cells is biased towards generating defective viruses which are expressed by DNA regulatory elements in the HIV genome. These studies describe an alternative mechanism for chronic expression of HIV genomes.

Provirus

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10.1101/2021.09.29.462330

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Using networks to measure similarity between genes: association index selection

Nature Methods (2013)

Juan I. Fuxman Bass Alos Diallo J. Daniel Nelson Juan M Soto Chad L. Myers

Jaccard index

Similarity (geometry)

Association (psychology)

Gene selection

10.1038/nmeth.2728

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Citations (244)

Enhanced Yeast One-Hybrid Assays to Study Protein–DNA Interactions

Methods in molecular biology (2022)

Anna Berenson Juan I. Fuxman Bass

genomic DNA

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10.1007/978-1-0716-2847-8_2

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Citations (5)

Emerging questions in transcriptional regulation

Cell Systems (2023)

Elphège P. Nora Stein Aerts Patricia J. Wittkopp Harmen J. Bussemaker Martha L. Bulyk

Ask price

10.1016/j.cels.2023.03.005

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A large-scale cancer-specific protein-DNA interaction network

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Yunwei Lu Anna Berenson Ryan Lane Isabelle Guelin Zhaorong Li

Abstract Cancer development and progression are generally associated with dysregulation of gene expression, often resulting from changes in transcription factor (TF) sequence or expression. Identifying key TFs involved in cancer gene regulation provides a framework for potential new therapeutics. This study presents a large-scale cancer gene TF-DNA interaction network as well as an extensive promoter clone resource for future studies. Most highly connected TFs do not show a preference for binding to promoters of genes associated with either good or poor cancer prognosis, suggesting that emerging strategies aimed at shifting gene expression balance between these two prognostic groups may be inherently complex. However, we identified potential for oncogene targeted therapeutics, with half of the tested oncogenes being potentially repressed by influencing specific activator or bifunctional TFs. Finally, we investigate the role of intrinsically disordered regions within the key cancer-related TF estrogen receptor ɑ (ESR1) on DNA binding and transcriptional activity, and found that these regions can have complex trade-offs in TF function. Altogether, our study not only broadens our knowledge of TFs involved in the cancer gene regulatory network but also provides a valuable resource for future studies, laying a foundation for potential therapeutic strategies targeting TFs in cancer.

Gene regulatory network

10.1101/2024.01.24.577099

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Mapping and analysis ofCaenorhabditis eleganstranscription factor sequence specificities

Kamesh Narasimhan Samuel A. Lambert Ally Yang Jeremy Riddell Sanié Mnaimneh

Sequence (biology)

Factor (programming language)

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Enhanced Yeast One-hybrid Screens To Identify Transcription Factor Binding To Human DNA Sequences

Journal of Visualized Experiments (2019)

Shaleen Shrestha Xing Liu Clarissa Stephanie Santoso Juan I. Fuxman Bass

Identifying the sets of transcription factors (TFs) that regulate each human gene is a daunting task that requires integrating numerous experimental and computational approaches. One such method is the yeast one-hybrid (Y1H) assay, in which interactions between TFs and DNA regions are tested in the milieu of the yeast nucleus using reporter genes. Y1H assays involve two components: a 'DNA-bait' (e.g., promoters, enhancers, silencers, etc.) and a 'TF-prey,' which can be screened for reporter gene activation. Most published protocols for performing Y1H screens are based on transforming TF-prey libraries or arrays into DNA-bait yeast strains. Here, we describe a pipeline, called enhanced Y1H (eY1H) assays, where TF-DNA interactions are interrogated by mating DNA-bait strains with an arrayed collection of TF-prey strains using a high density array (HDA) robotic platform that allows screening in a 1,536 colony format. This allows for a dramatic increase in throughput (60 DNA-bait sequences against >1,000 TFs takes two weeks per researcher) and reproducibility. We illustrate the different types of expected results by testing human promoter sequences against an array of 1,086 human TFs, as well as examples of issues that can arise during screens and how to troubleshoot them.

DNA binding site

10.3791/59192

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Characterization of bacterial DNA binding to human neutrophil surface

Laboratory Investigation (2008)

Juan I. Fuxman Bass María Laura Gabelloni María Eugenia Dies Álvarez Mónica Vermeulen Daniela M. Russo

Neutrophil Extracellular Traps

10.1038/labinvest.2008.59

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Citations (21)