Full Text Journal Articles by
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Dynamic chromatin regulatory landscape of human CAR T cell exhaustion.

David G Gennert, Rachel C Lynn, Jeff M Granja, Evan W Weber, Maxwell R Mumbach, Yang Zhao, Zhana Duren, Elena Sotillo, William J Greenleaf, Wing H Wong, Ansuman T Satpathy, Crystal L Mackall, Howard Y Chang,

Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found ... Read more >>

Proc Natl Acad Sci U S A (Proceedings of the National Academy of Sciences of the United States of America)
[2021, 118(30):]

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Author Correction: ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis.

Jeffrey M Granja, M Ryan Corces, Sarah E Pierce, S Tansu Bagdatli, Hani Choudhry, Howard Y Chang, William J Greenleaf,

Nat Genet (Nature genetics)
[2021, 53(6):935]

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

Aaron J Wilk, Madeline J Lee, Bei Wei, Benjamin Parks, Ruoxi Pi, Giovanny J Martínez-Colón, Thanmayi Ranganath, Nancy Q Zhao, Shalina Taylor, Winston Becker, , David Jimenez-Morales, Andra L Blomkalns, Ruth O'Hara, Euan A Ashley, Kari C Nadeau, Samuel Yang, Susan Holmes, Marlene Rabinovitch, Angela J Rogers, William J Greenleaf, Catherine A Blish,

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease ... Read more >>

J Exp Med (The Journal of experimental medicine)
[2021, 218(8):]

Cited: 3 times

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Multi-omic Analysis of Familial Adenomatous Polyposis Reveals Molecular Pathways and Polyclonal Spreading Associated with Early Tumorigenesis

Michael Snyder, Aaron Horning, Edward Esplin, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Nevins, Lihua Jiang, Kevin Contrepoi, Hayan Lee, Tuhin Guha, Zheng Hu, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Joanne Chan, Mathew Ellenberger, Aziz Khan, Basil Michael, Bahareh Bahmani, Glen Esplin, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri Longacre, William Greenleaf, Christina Curtis, James Ford, Winston Becker,

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected patients, leading to colorectal cancer (CRC), and is an ideal model to study early transition to CRC. We performed deep multi-omic profiling of 135 normal mucosal, benign and dysplastic polyps and adenocarcinoma samples from 6 ... Read more >>

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Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks

Jacob Freimer, Oren Shaked, Sahin Naqvi, Nasa Sinnott-Armstrong, Arwa Kathiria, Amy Chen, Jessica Cortez, William Greenleaf, Jonathan Pritchard, Alexander Marson,

<h4>Summary</h4> Complex gene regulatory networks ensure that important genes are expressed at precise levels. When gene expression is sufficiently perturbed it can lead to disease. To understand how gene expression disruptions percolate through a network, we must first map connections between regulatory genes and their downstream targets. However, we lack ... Read more >>

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Direct profiling of genome-wide dCas9 and Cas9 specificity using ssDNA mapping (CasKAS)

Georgi Marinov, Samuel Kim, Tansu Bagdatli, Alexandro Trevino, Josh Tycko, Tong Wu, Lacramioara Bintu, Michael Bassik, Chuan He, Anshul Kundaje, William Greenleaf,

Detecting and mitigating off-target activity is critical to the practical application of CRISPR-mediated genome and epigenome editing. While numerous methods have been developed to map Cas9 binding specificity genome-wide, they are generally time-consuming and/or expensive, and not applicable to catalytically dead CRISPR enzymes. We have developed a rapid, inexpensive, and ... Read more >>

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High-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer.

Sarah E Pierce, Jeffrey M Granja, William J Greenleaf,

Chromatin accessibility profiling can identify putative regulatory regions genome wide; however, pooled single-cell methods for assessing the effects of regulatory perturbations on accessibility are limited. Here, we report a modified droplet-based single-cell ATAC-seq protocol for perturbing and evaluating dynamic single-cell epigenetic states. This method (Spear-ATAC) enables simultaneous read-out of chromatin ... Read more >>

Nat Commun (Nature communications)
[2021, 12(1):2969]

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Transcription-dependent domain-scale three-dimensional genome organization in the dinoflagellate Breviolum minutum.

Georgi K Marinov, Alexandro E Trevino, Tingting Xiang, Anshul Kundaje, Arthur R Grossman, William J Greenleaf,

Dinoflagellate chromosomes represent a unique evolutionary experiment, as they exist in a permanently condensed, liquid crystalline state; are not packaged by histones; and contain genes organized into tandem gene arrays, with minimal transcriptional regulation. We analyze the three-dimensional genome of Breviolum minutum, and find large topological domains (dinoflagellate topologically associating ... Read more >>

Nat Genet (Nature genetics)
[2021, 53(5):613-617]

Cited: 1 time

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Dynamic chromatin regulatory landscape of human CAR T cell exhaustion

David Gennert, Rachel Lynn, Jeff Granja, Evan Weber, Maxwell Mumbach, Yang Zhao, Zhana Duren, Elena Sotillo, William Greenleaf, Wing Wong, Ansuman Satpathy, Crystal Mackall, Howard Chang,

<h4>ABSTRACT</h4> Dysfunction in T cells limits the efficacy of cancer immunotherapy 1–6 . We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo ... Read more >>

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LKB1 inactivation modulates chromatin accessibility to drive metastatic progression

Sarah Pierce, Jeffrey Granja, Ryan Corces, Jennifer Brady, Min Tsai, Aubrey Pierce, Rui Tang, Pauline Chu, David Feldser, Howard Chang, Michael Bassik, William Greenleaf, Monte Winslow,

Metastasis is the leading cause of cancer-related deaths, enabling cancer cells to expand to secondary sites and compromise organ function 1 . Given that primary tumors and metastases often share the same constellation of driver mutations 2–4 , the mechanisms driving their distinct phenotypes are unclear. Here, we show that ... Read more >>

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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Chiung-Ying Chang, Zohar Shipony, Ann Kuo, Kyle Loh, William Greenleaf, Gerald Crabtree,

<h4>Summary</h4> Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads ... Read more >>

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Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

Winston Becker, Stephanie Nevins, Derek Chen, Roxanne Chiu, Aaron Horning, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward Esplin, Anshul Kundaje, James Ford, Christina Curtis, Michael Snyder, William Greenleaf,

<h4>ABSTRACT</h4> To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without ... Read more >>

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Integrating transcription factor abundance with chromatin accessibility in human erythroid lineage commitment

Reema Baskar, Amy Chen, Patricia Favaro, Warren Reynolds, Fabian Mueller, Luciene Borges, Sizun Jiang, Hyun Shin Park, Eric Kool, William Greenleaf, Sean Bendall,

We present InTAC-seq, a method for simultaneous quantification of genome-wide open chromatin and intracellular protein abundance in fixed cells. Using InTAC we directly observe variation in chromatin accessibility and transcription factor motif occupancy driven by differences in transcription factor protein abundance. By purifying bone marrow progenitor cells based on GATA1 ... Read more >>

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Quantification of Cas9 binding and cleavage across diverse guide sequences maps landscapes of target engagement.

Evan A Boyle, Winston R Becker, Hua B Bai, Janice S Chen, Jennifer A Doudna, William J Greenleaf,

The RNA-guided nuclease Cas9 has unlocked powerful methods for perturbing both the genome through targeted DNA cleavage and the regulome through targeted DNA binding, but limited biochemical data have hampered efforts to quantitatively model sequence perturbation of target binding and cleavage across diverse guide sequences. We present scalable, sequencing-based platforms ... Read more >>

Sci Adv (Science advances)
[2021, 7(8):]

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Integrated single-cell transcriptomics and epigenomics reveals strong germinal center-associated etiology of autoimmune risk loci

Hamish King, Kristen Wells, Zohar Shipony, Arwa Kathiria, Lisa Wagar, Caleb Lareau, Nara Orban, Robson Capasso, Mark Davis, Lars Steinmetz, Louisa James, William Greenleaf,

The germinal center (GC) response is critical for both effective adaptive immunity and establishing peripheral tolerance by limiting auto-reactive B cells. Dysfunction in these processes can lead to defects in immune response to pathogens or contribute to autoimmune disease. To understand the gene regulatory principles underlying the GC response, we ... Read more >>

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ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis.

Jeffrey M Granja, M Ryan Corces, Sarah E Pierce, S Tansu Bagdatli, Hani Choudhry, Howard Y Chang, William J Greenleaf,

The advent of single-cell chromatin accessibility profiling has accelerated the ability to map gene regulatory landscapes but has outpaced the development of scalable software to rapidly extract biological meaning from these data. Here we present a software suite for single-cell analysis of regulatory chromatin in R (ArchR; https://www.archrproject.com/ ) that ... Read more >>

Nat Genet (Nature genetics)
[2021, 53(3):403-411]

Cited: 9 times

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Building a high-quality Human Cell Atlas.

Orit Rozenblatt-Rosen, Jay W Shin, Jennifer E Rood, Anna Hupalowska, , Aviv Regev, Holger Heyn,

Nat Biotechnol (Nature biotechnology)
[2021, 39(2):149-153]

Cited: 1 time

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Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons.

Jacob A Blum, Sandy Klemm, Jennifer L Shadrach, Kevin A Guttenplan, Lisa Nakayama, Arwa Kathiria, Phuong T Hoang, Olivia Gautier, Julia A Kaltschmidt, William J Greenleaf, Aaron D Gitler,

The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting ... Read more >>

Nat Neurosci (Nature neuroscience)
[2021, 24(4):572-583]

Cited: 2 times

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Finding needles in a haystack: dissecting tumor heterogeneity with single-cell transcriptomic and chromatin accessibility profiling.

Sarah E Pierce, Samuel H Kim, William J Greenleaf,

Tumor evolution often results in a wealth of heterogeneous cancer cell types within a single tumor - heterogeneity that can include epigenetic and gene expression changes that are impossible to identify from histological features alone. The invasion of cancer cells into nearby healthy tissue, accompanied by the infiltration of responding ... Read more >>

Curr Opin Genet Dev (Current opinion in genetics & development)
[2021, 66:36-40]

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Chromatin and gene-regulatory dynamics of the developing human cerebral cortex at single-cell resolution

Alexandro Trevino, Fabian Müller, Jimena Andersen, Laksshman Sundaram, Arwa Kathiria, Anna Shcherbina, Kyle Farh, Howard Chang, Anca Paşca, Anshul Kundaje, Sergiu Paşca, William Greenleaf,

<h4>ABSTRACT</h4> Genetic perturbations of cerebral cortical development can lead to neurodevelopmental disease, including autism spectrum disorder (ASD). To identify genomic regions crucial to corticogenesis, we mapped the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility both independently and jointly. This revealed waves of gene ... Read more >>

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p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR).

Maya Maor-Nof, Zohar Shipony, Rodrigo Lopez-Gonzalez, Lisa Nakayama, Yong-Jie Zhang, Julien Couthouis, Jacob A Blum, Patricia A Castruita, Gabriel R Linares, Kai Ruan, Gokul Ramaswami, David J Simon, Aviv Nof, Manuel Santana, Kyuho Han, Nasa Sinnott-Armstrong, Michael C Bassik, Daniel H Geschwind, Marc Tessier-Lavigne, Laura D Attardi, Thomas E Lloyd, Justin K Ichida, Fen-Biao Gao, William J Greenleaf, Jennifer S Yokoyama, Leonard Petrucelli, Aaron D Gitler,

The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein ... Read more >>

Cell (Cell)
[2021, 184(3):689-708.e20]

Cited: 5 times

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Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

Aaron Wilk, Madeline Lee, Bei Wei, Benjamin Parks, Ruoxi Pi, Giovanny Martínez-Colón, Thanmayi Ranganath, Nancy Zhao, Shalina Taylor, Winston Becker, David Jimenez-Morales, Andra Blomkalns, Ruth O’Hara, Euan Ashley, Kari Nadeau, Samuel Yang, Susan Holmes, Marlene Rabinovitch, Angela Rogers, William Greenleaf, Catherine Blish, ,

<h4>ABSTRACT</h4> Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of ... Read more >>

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High-throughput single-cell chromatin accessibility CRISPR screens enable unbiased identification of regulatory networks in cancer

Sarah Pierce, Jeffrey Granja, William Greenleaf,

Spear-ATAC is a modified droplet-based single-cell ATAC-seq (scATAC-seq) protocol that enables simultaneous read-out of chromatin accessibility profiles and integrated sgRNA spacer sequences from thousands of individual cells at a time. Spear-ATAC profiling of 104,592 cells representing 414 sgRNA knock-down populations revealed the temporal dynamics of epigenetic responses to regulatory perturbations ... Read more >>

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Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer's and Parkinson's diseases.

M Ryan Corces, Anna Shcherbina, Soumya Kundu, Michael J Gloudemans, Laure Frésard, Jeffrey M Granja, Bryan H Louie, Tiffany Eulalio, Shadi Shams, S Tansu Bagdatli, Maxwell R Mumbach, Boxiang Liu, Kathleen S Montine, William J Greenleaf, Anshul Kundaje, Stephen B Montgomery, Howard Y Chang, Thomas J Montine,

Genome-wide association studies of neurological diseases have identified thousands of variants associated with disease phenotypes. However, most of these variants do not alter coding sequences, making it difficult to assign their function. Here, we present a multi-omic epigenetic atlas of the adult human brain through profiling of single-cell chromatin accessibility ... Read more >>

Nat Genet (Nature genetics)
[2020, 52(11):1158-1168]

Cited: 10 times

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The dynamic, combinatorial cis-regulatory lexicon of epidermal differentiation

Daniel Kim, Viviana Risca, David Reynolds, James Chappell, Adam Rubin, Namyoung Jung, Laura Donohue, Arwa Kathiria, Minyi Shi, Zhixin Zhao, Harsh Deep, Howard Chang, Michael Snyder, William Greenleaf, Anshul Kundaje, Paul Khavari,

Transcription factors (TFs) bind DNA sequence motif vocabularies in cis-regulatory elements (CREs) to modulate chromatin state and gene expression during cell state transitions. A quantitative understanding of how motif lexicons influence dynamic regulatory activity has been elusive due to the combinatorial nature of the cis-regulatory code. To address this, we ... Read more >>

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