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Article ; Online: Scalable genetic screening for regulatory circuits using compressed Perturb-seq.

Yao, Douglas / Binan, Loic / Bezney, Jon / Simonton, Brooke / Freedman, Jahanara / Frangieh, Chris J / Dey, Kushal / Geiger-Schuller, Kathryn / Eraslan, Basak / Gusev, Alexander / Regev, Aviv / Cleary, Brian

Nature biotechnology

2023

Abstract: Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited in scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq ... ...

Abstract	Pooled CRISPR screens with single-cell RNA sequencing readout (Perturb-seq) have emerged as a key technique in functional genomics, but they are limited in scale by cost and combinatorial complexity. In this study, we modified the design of Perturb-seq by incorporating algorithms applied to random, low-dimensional observations. Compressed Perturb-seq measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq with an order of magnitude cost reduction and greater power to learn genetic interactions. We identified known and novel regulators of immune responses and uncovered evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing genome-wide association studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.
Language	English
Publishing date	2023-10-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-023-01964-9
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Article: Compressed Perturb-seq: highly efficient screens for regulatory circuits using random composite perturbations.

bioRxiv : the preprint server for biology

2023

Abstract: Pooled CRISPR screens with single-cell RNA-seq readout (Perturb-seq) have emerged as a key technique in functional genomics, but are limited in scale by cost and combinatorial complexity. Here, we reimagine Perturb-seq's design through the lens of ... ...

Abstract	Pooled CRISPR screens with single-cell RNA-seq readout (Perturb-seq) have emerged as a key technique in functional genomics, but are limited in scale by cost and combinatorial complexity. Here, we reimagine Perturb-seq's design through the lens of algorithms applied to random, low-dimensional observations. We present compressed Perturb-seq, which measures multiple random perturbations per cell or multiple cells per droplet and computationally decompresses these measurements by leveraging the sparse structure of regulatory circuits. Applied to 598 genes in the immune response to bacterial lipopolysaccharide, compressed Perturb-seq achieves the same accuracy as conventional Perturb-seq at 4 to 20-fold reduced cost, with greater power to learn genetic interactions. We identify known and novel regulators of immune responses and uncover evolutionarily constrained genes with downstream targets enriched for immune disease heritability, including many missed by existing GWAS or trans-eQTL studies. Our framework enables new scales of interrogation for a foundational method in functional genomics.
Language	English
Publishing date	2023-01-23
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.23.525200
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Book ; Online ; Thesis: Deciphering the genetic code of post-transcriptional gene expression regulation via multi-omics data integration

Eraslan, Basak Verfasser] / [Gagneur, Julien [Akademischer Betreuer] / Gagneur, Julien [Gutachter] / Wilhelm, Mathias [Gutachter]

2021

Author's details	Basak Eraslan ; Gutachter: Julien Gagneur, Mathias Wilhelm ; Betreuer: Julien Gagneur
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Publisher	Universitätsbibliothek der TU München
Publishing place	München
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article ; Online: Remodeling of colon plasma cell repertoire within ulcerative colitis patients.

Scheid, Johannes F / Eraslan, Basak / Hudak, Andrew / Brown, Eric M / Sergio, Dallis / Delorey, Toni M / Phillips, Devan / Lefkovith, Ariel / Jess, Alison T / Duck, Lennard W / Elson, Charles O / Vlamakis, Hera / Plichta, Damian R / Deguine, Jacques / Ananthakrishnan, Ashwin N / Graham, Daniel B / Regev, Aviv / Xavier, Ramnik J

The Journal of experimental medicine

2023 Volume 220, Issue 4

Abstract: Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We ... ...

Abstract	Plasma cells (PCs) constitute a significant fraction of colonic mucosal cells and contribute to inflammatory infiltrates in ulcerative colitis (UC). While gut PCs secrete bacteria-targeting IgA antibodies, their role in UC pathogenesis is unknown. We performed single-cell V(D)J- and RNA-seq on sorted B cells from the colon of healthy individuals and patients with UC. A large fraction of B cell clones is shared between different colon regions, but inflammation in UC broadly disrupts this landscape, causing transcriptomic changes characterized by an increase in the unfolded protein response (UPR) and antigen presentation genes, clonal expansion, and isotype skewing from IgA1 and IgA2 to IgG1. We also directly expressed and assessed the specificity of 152 mAbs from expanded PC clones. These mAbs show low polyreactivity and autoreactivity and instead target both shared bacterial antigens and specific bacterial strains. Altogether, our results characterize the microbiome-specific colon PC response and how its disruption might contribute to inflammation in UC.
MeSH term(s)	Humans ; Colitis, Ulcerative/genetics ; Plasma Cells ; Colon ; Inflammation/metabolism ; Antigens, Bacterial ; Bacteria ; Immunoglobulin A/metabolism ; Intestinal Mucosa
Chemical Substances	Antigens, Bacterial ; Immunoglobulin A
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	218343-2
ISSN	1540-9538 ; 0022-1007
ISSN (online)	1540-9538
ISSN	0022-1007
DOI	10.1084/jem.20220538
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Article ; Online: HLA-II immunopeptidome profiling and deep learning reveal features of antigenicity to inform antigen discovery.

Stražar, Martin / Park, Jihye / Abelin, Jennifer G / Taylor, Hannah B / Pedersen, Thomas K / Plichta, Damian R / Brown, Eric M / Eraslan, Basak / Hung, Yuan-Mao / Ortiz, Kayla / Clauser, Karl R / Carr, Steven A / Xavier, Ramnik J / Graham, Daniel B

Immunity

2023 Volume 56, Issue 7, Page(s) 1681–1698.e13

Abstract: CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete ... ...

Abstract	CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.
MeSH term(s)	Humans ; Captan ; Deep Learning ; COVID-19 ; SARS-CoV-2 ; HLA Antigens ; Epitopes, T-Lymphocyte ; Peptides
Chemical Substances	Captan (EOL5G26Q9F) ; HLA Antigens ; Epitopes, T-Lymphocyte ; Peptides
Language	English
Publishing date	2023-06-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2023.05.009
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Article: Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq.

bioRxiv : the preprint server for biology

2023

Abstract: E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the ... ...

Abstract	E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the balance of DC1, DC2, migratory DC and macrophage states and a gradient of DC maturation. Family members grouped into co-functional modules that were enriched for physical interactions and impacted specific programs through substrate transcription factors. E3s and their adaptors co-regulated the same processes, but partnered with different substrate recognition adaptors to impact distinct aspects of the DC life cycle. Genetic interactions were more prevalent within than between modules, and a deep learning model, comβVAE, predicts the outcome of new combinations by leveraging modularity. The E3 regulatory network was associated with heritable variation and aberrant gene expression in immune cells in human inflammatory diseases. Our study provides a general approach to dissect gene function.
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.23.525198
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Functional analyses and single cell immunoprofiling uncover sex-specific differences in SARS-CoV2 immune memory development.

Eraslan, Basak / Brown, Eric / Benson, Maura / Amir-Zilberstein, Liat / Park, Sung-Moo / Tusi, Betsabeh / Pokatayev, Vladislav / Hecht, Cody / Pishesha, Novalia / Phillips, Devan / Kim, Andy / Zhang, Shuting / Gaca, Anthony / Ghantous, Fadi / Delorey, Toni / Livny, Jonathan / Baden, Lindsey / Rozenblatt-Rosen, Orit / Graham, Daniel /

Regev, Aviv / Seaman, Michael / Woolley, Ann / Cosimi, Lisa / Hung, Deborah / Deguine, Jacques / Xavier, Ramnik

Research square

2022

Abstract: SARS-CoV-2 infection leads to a broad range of outcomes and immune responses, with the development of neutralizing antibodies generally correlated with protection against reinfection. Here, we have characterized both neutralizing activity and T cell ... ...

Abstract	SARS-CoV-2 infection leads to a broad range of outcomes and immune responses, with the development of neutralizing antibodies generally correlated with protection against reinfection. Here, we have characterized both neutralizing activity and T cell responses in a cluster of subjects with mild disease linked to a single spreading event. Surprisingly, we observed sex-specific associations between spike- and particularly nucleoprotein-specific T cell responses and neutralization, with pro-inflammatory cytokines being linked to higher titers only in males. Using single cell immunoprofiling, which provided matched transcriptome and T-cell receptor (TCR) profiles in restimulated CD4 + and CD8 + cells from these subjects, we identified differences in type I IFN signaling that may underlie this difference in antibody generation. Finally, we also identified several TCRs associated with cytokine producing T cells. Altogether, our work maps the breadth of immunological outcomes of SARS-CoV2 infections and highlight the potential role of sex-specific feedback loops during the generation of neutralizing antibodies.
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-1416969/v1
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Article ; Online: Quantification and discovery of sequence determinants of protein-per-mRNA amount in 29 human tissues.

Eraslan, Basak / Wang, Dongxue / Gusic, Mirjana / Prokisch, Holger / Hallström, Björn M / Uhlén, Mathias / Asplund, Anna / Pontén, Frederik / Wieland, Thomas / Hopf, Thomas / Hahne, Hannes / Kuster, Bernhard / Gagneur, Julien

Molecular systems biology

2019 Volume 15, Issue 2, Page(s) e8513

Abstract: Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins ...

Abstract	Despite their importance in determining protein abundance, a comprehensive catalogue of sequence features controlling protein-to-mRNA (PTR) ratios and a quantification of their effects are still lacking. Here, we quantified PTR ratios for 11,575 proteins across 29 human tissues using matched transcriptomes and proteomes. We estimated by regression the contribution of known sequence determinants of protein synthesis and degradation in addition to 45 mRNA and 3 protein sequence motifs that we found by association testing. While PTR ratios span more than 2 orders of magnitude, our integrative model predicts PTR ratios at a median precision of 3.2-fold. A reporter assay provided functional support for two novel UTR motifs, and an immobilized mRNA affinity competition-binding assay identified motif-specific bound proteins for one motif. Moreover, our integrative model led to a new metric of codon optimality that captures the effects of codon frequency on protein synthesis and degradation. Altogether, this study shows that a large fraction of PTR ratio variation in human tissues can be predicted from sequence, and it identifies many new candidate post-transcriptional regulatory elements.
MeSH term(s)	Gene Expression Regulation/genetics ; Genome, Human/genetics ; Humans ; Mass Spectrometry/methods ; Proteins/genetics ; Proteome/genetics ; Proteomics/methods ; RNA, Messenger/genetics ; Sequence Analysis, RNA/methods ; Tissue Distribution/genetics ; Transcriptome/genetics
Chemical Substances	Proteins ; Proteome ; RNA, Messenger
Language	English
Publishing date	2019-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.20188513
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A deep proteome and transcriptome abundance atlas of 29 healthy human tissues.

Wang, Dongxue / Eraslan, Basak / Wieland, Thomas / Hallström, Björn / Hopf, Thomas / Zolg, Daniel Paul / Zecha, Jana / Asplund, Anna / Li, Li-Hua / Meng, Chen / Frejno, Martin / Schmidt, Tobias / Schnatbaum, Karsten / Wilhelm, Mathias / Ponten, Frederik / Uhlen, Mathias / Gagneur, Julien / Hahne, Hannes / Kuster, Bernhard

Molecular systems biology

2019 Volume 15, Issue 2, Page(s) e8503

Abstract: Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully ... ...

Abstract	Genome-, transcriptome- and proteome-wide measurements provide insights into how biological systems are regulated. However, fundamental aspects relating to which human proteins exist, where they are expressed and in which quantities are not fully understood. Therefore, we generated a quantitative proteome and transcriptome abundance atlas of 29 paired healthy human tissues from the Human Protein Atlas project representing human genes by 18,072 transcripts and 13,640 proteins including 37 without prior protein-level evidence. The analysis revealed that hundreds of proteins, particularly in testis, could not be detected even for highly expressed mRNAs, that few proteins show tissue-specific expression, that strong differences between mRNA and protein quantities within and across tissues exist and that protein expression is often more stable across tissues than that of transcripts. Only 238 of 9,848 amino acid variants found by exome sequencing could be confidently detected at the protein level showing that proteogenomics remains challenging, needs better computational methods and requires rigorous validation. Many uses of this resource can be envisaged including the study of gene/protein expression regulation and biomarker specificity evaluation.
MeSH term(s)	Gene Expression Regulation/genetics ; Genome, Human/genetics ; Humans ; Mass Spectrometry/methods ; Proteome/genetics ; Proteomics/methods ; RNA, Messenger/genetics ; Sequence Analysis, RNA/methods ; Tissue Distribution/genetics ; Transcriptome/genetics
Chemical Substances	Proteome ; RNA, Messenger
Language	English
Publishing date	2019-02-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2193510-5
ISSN	1744-4292 ; 1744-4292
ISSN (online)	1744-4292
ISSN	1744-4292
DOI	10.15252/msb.20188503
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Scheid, Johannes F / Barnes, Christopher O / Eraslan, Basak / Hudak, Andrew / Keeffe, Jennifer R / Cosimi, Lisa A / Brown, Eric M / Muecksch, Frauke / Weisblum, Yiska / Zhang, Shuting / Delorey, Toni / Woolley, Ann E / Ghantous, Fadi / Park, Sung-Moo / Phillips, Devan / Tusi, Betsabeh / Huey-Tubman, Kathryn E / Cohen, Alexander A / Gnanapragasam, Priyanthi N.P /

Rzasa, Kara / Hatziioanno, Theodora / Durney, Michael A / Gu, Xiebin / Tada, Takuya / Landau, Nathaniel R / West, Anthony P / Rozenblatt-Rosen, Orit / Seaman, Michael S / Baden, Lindsey R / Graham, Daniel B / Deguine, Jacques / Bieniasz, Paul D / Regev, Aviv / Hung, Deborah / Bjorkman, Pamela J / Xavier, Ramnik J

Cell. 2021 June 10, v. 184, no. 12

2021

Abstract: Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and ...

Abstract	Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.
Keywords	B-lymphocytes ; RNA ; Severe acute respiratory syndrome coronavirus 2 ; cryo-electron microscopy ; epitopes ; genomics ; memory ; sequence analysis ; therapeutics ; transcription (genetics) ; vaccines
Language	English
Dates of publication	2021-0610
Size	p. 3205-3221.e24.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2021.04.032
Database	NAL-Catalogue (AGRICOLA)

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