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Article ; Online: Estimating pseudocounts and fold changes for digital expression measurements.

Erhard, Florian

2018 Volume 34, Issue 23, Page(s) 4054–4063

Abstract: Motivation: Fold changes from count based high-throughput experiments such as RNA-seq suffer from a zero-frequency problem. To circumvent division by zero, so-called pseudocounts are added to make all observed counts strictly positive. The magnitude of ... ...

Abstract	Motivation: Fold changes from count based high-throughput experiments such as RNA-seq suffer from a zero-frequency problem. To circumvent division by zero, so-called pseudocounts are added to make all observed counts strictly positive. The magnitude of pseudocounts for digital expression measurements and on which stage of the analysis they are introduced remained an arbitrary choice. Moreover, in the strict sense, fold changes are not quantities that can be computed. Instead, due to the stochasticity involved in the experiments, they must be estimated by statistical inference. Results: Here, we build on a statistical framework for fold changes, where pseudocounts correspond to the parameters of the prior distribution used for Bayesian inference of the fold change. We show that arbitrary and widely used choices for applying pseudocounts can lead to biased results. As a statistical rigorous alternative, we propose and test an empirical Bayes procedure to choose appropriate pseudocounts. Moreover, we introduce the novel estimator Ψ LFC for fold changes showing favorable properties with small counts and smaller deviations from the truth in simulations and real data compared to existing methods. Our results have direct implications for entities with few reads in sequencing experiments, and indirectly also affect results for entities with many reads. Availability and implementation: Ψ LFC is available as an R package under https://github.com/erhard-lab/lfc (Apache 2.0 license); R scripts to generate all figures are available at zenodo (doi: 10.5281/zenodo.1163029). Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Bayes Theorem ; Computational Biology ; RNA ; Sequence Analysis, RNA
Chemical Substances	RNA (63231-63-0)
Language	English
Publishing date	2018-06-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/bty471
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Article ; Online: Integrative transcription start site identification with iTiSS.

Jürges, Christopher S / Dölken, Lars / Erhard, Florian

Bioinformatics (Oxford, England)

2023 Volume 37, Issue 18, Page(s) 3056–3057

Abstract: Summary: Many experimental approaches have been developed to identify transcription start sites (TSS) from genomic scale data. However, experiment specific biases lead to large numbers of false-positive calls. Here, we present our integrative approach ... ...

Abstract	Summary: Many experimental approaches have been developed to identify transcription start sites (TSS) from genomic scale data. However, experiment specific biases lead to large numbers of false-positive calls. Here, we present our integrative approach iTiSS, which is an accurate and generic TSS caller for any TSS profiling experiment in eukaryotes, and substantially reduces the number of false positives by a joint analysis of several complementary datasets. Availability and implementation: iTiSS is platform independent and implemented in Java (v1.8) and is freely available at https://www.erhard-lab.de/software and https://github.com/erhard-lab/iTiSS. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Software ; Transcription Initiation Site ; Genomics ; Eukaryota
Language	English
Publishing date	2023-01-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btab170
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Article ; Online: grandR: a comprehensive package for nucleotide conversion RNA-seq data analysis.

Rummel, Teresa / Sakellaridi, Lygeri / Erhard, Florian

Nature communications

2023 Volume 14, Issue 1, Page(s) 3559

Abstract: Metabolic labeling of RNA is a powerful technique for studying the temporal dynamics of gene expression. Nucleotide conversion approaches greatly facilitate the generation of data but introduce challenges for their analysis. Here we present grandR, a ... ...

Abstract	Metabolic labeling of RNA is a powerful technique for studying the temporal dynamics of gene expression. Nucleotide conversion approaches greatly facilitate the generation of data but introduce challenges for their analysis. Here we present grandR, a comprehensive package for quality control, differential gene expression analysis, kinetic modeling, and visualization of such data. We compare several existing methods for inference of RNA synthesis rates and half-lives using progressive labeling time courses. We demonstrate the need for recalibration of effective labeling times and introduce a Bayesian approach to study the temporal dynamics of RNA using snapshot experiments.
MeSH term(s)	RNA-Seq ; Gene Expression Profiling/methods ; Software ; Nucleotides/genetics ; Bayes Theorem ; Sequence Analysis, RNA/methods ; RNA/genetics
Chemical Substances	Nucleotides ; RNA (63231-63-0)
Language	English
Publishing date	2023-06-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39163-4
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Article ; Online: Estimating pseudocounts and fold changes for digital expression measurements

Erhard, Florian

Bioinformatics. 2018 Dec. 01, v. 34, no. 23, p. 4054-4063

2018 , Page(s) 4054–4063

Abstract: Fold changes from count based high-throughput experiments such as RNA-seq suffer from a zero-frequency problem. To circumvent division by zero, so-called pseudocounts are added to make all observed counts strictly positive. The magnitude of pseudocounts ... ...

Abstract	Fold changes from count based high-throughput experiments such as RNA-seq suffer from a zero-frequency problem. To circumvent division by zero, so-called pseudocounts are added to make all observed counts strictly positive. The magnitude of pseudocounts for digital expression measurements and on which stage of the analysis they are introduced remained an arbitrary choice. Moreover, in the strict sense, fold changes are not quantities that can be computed. Instead, due to the stochasticity involved in the experiments, they must be estimated by statistical inference. Here, we build on a statistical framework for fold changes, where pseudocounts correspond to the parameters of the prior distribution used for Bayesian inference of the fold change. We show that arbitrary and widely used choices for applying pseudocounts can lead to biased results. As a statistical rigorous alternative, we propose and test an empirical Bayes procedure to choose appropriate pseudocounts. Moreover, we introduce the novel estimator Ψ LFC for fold changes showing favorable properties with small counts and smaller deviations from the truth in simulations and real data compared to existing methods. Our results have direct implications for entities with few reads in sequencing experiments, and indirectly also affect results for entities with many reads. Ψ LFC is available as an R package under https://github.com/erhard-lab/lfc (Apache 2.0 license); R scripts to generate all figures are available at zenodo (doi: 10.5281/zenodo.1163029). Supplementary data are available at Bioinformatics online.
Keywords	Bayesian theory ; bioinformatics ; sequence analysis ; statistical inference
Language	English
Dates of publication	2018-1201
Size	p. 4054-4063
Publishing place	Oxford University Press
Document type	Article ; Online
ZDB-ID	1468345-3
ISSN	1367-4811 ; 1460-2059
ISSN	1367-4811 ; 1460-2059
DOI	10.1093/bioinformatics/bty471
Database	NAL-Catalogue (AGRICOLA)

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Article: The Hidden Enemy Within: Non-canonical Peptides in Virus-Induced Autoimmunity.

Lodha, Manivel / Erhard, Florian / Dölken, Lars / Prusty, Bhupesh K

Frontiers in microbiology

2022 Volume 13, Page(s) 840911

Abstract: Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering ... ...

Abstract	Viruses play a key role in explaining the pathogenesis of various autoimmune disorders, whose underlying principle is defined by the activation of autoreactive T-cells. In many cases, T-cells escape self-tolerance due to the failure in encountering certain MHC-I self-peptide complexes at substantial levels, whose peptides remain invisible from the immune system. Over the years, contribution of unstable defective ribosomal products (DRiPs) in immunosurveillance has gained prominence. A class of unstable products emerge from non-canonical translation and processing of unannotated mammalian and viral ORFs and their peptides are cryptic in nature. Indeed, high throughput sequencing and proteomics have revealed that a substantial portion of our genomes comprise of non-canonical ORFs, whose generation is significantly modulated during disease. Many of these ORFs comprise short ORFs (sORFs) and upstream ORFs (uORFs) that resemble DRiPs and may hence be preferentially presented. Here, we discuss how such products, normally "hidden" from the immune system, become abundant in viral infections activating autoimmune T-cells, by discussing their emerging role in infection and disease. Finally, we provide a perspective on how these mechanisms can explain several autoimmune disorders in the wake of the COVID-19 pandemic.
Language	English
Publishing date	2022-02-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587354-4
ISSN	1664-302X
ISSN	1664-302X
DOI	10.3389/fmicb.2022.840911
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Single-cell temporal dynamics reveals the relative contributions of transcription and degradation to cell-type specific gene expression in zebrafish embryos.

Fishman, Lior / Nechooshtan, Gal / Erhard, Florian / Regev, Aviv / Farrell, Jeffrey A / Rabani, Michal

bioRxiv : the preprint server for biology

2023

Abstract: During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the underlying regulation of mRNA transcription and degradation remains a challenge, ... ...

Abstract	During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the underlying regulation of mRNA transcription and degradation remains a challenge, especially within whole embryos with diverse cellular identities. Here, we collect temporal cellular transcriptomes of zebrafish embryos, and decompose them into their newly-transcribed (zygotic) and pre-existing (maternal) mRNA components by combining single-cell RNA-Seq and metabolic labeling. We introduce kinetic models capable of quantifying regulatory rates of mRNA transcription and degradation within individual cell types during their specification. These reveal different regulatory rates between thousands of genes, and sometimes between cell types, that shape spatio-temporal expression patterns. Transcription drives most cell-type restricted gene expression. However, selective retention of maternal transcripts helps to define the gene expression profiles of germ cells and enveloping layer cells, two of the earliest specified cell-types. Coordination between transcription and degradation restricts expression of maternal-zygotic genes to specific cell types or times, and allows the emergence of spatio-temporal patterns when overall mRNA levels are held relatively constant. Sequence-based analysis links differences in degradation to specific sequence motifs. Our study reveals mRNA transcription and degradation events that control embryonic gene expression, and provides a quantitative approach to study mRNA regulation during a dynamic spatio-temporal response.
Language	English
Publishing date	2023-04-21
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.20.537620
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Article ; Online: Cell-type-specific mRNA transcription and degradation kinetics in zebrafish embryogenesis from metabolically labeled single-cell RNA-seq.

Fishman, Lior / Modak, Avani / Nechooshtan, Gal / Razin, Talya / Erhard, Florian / Regev, Aviv / Farrell, Jeffrey A / Rabani, Michal

Nature communications

2024 Volume 15, Issue 1, Page(s) 3104

Abstract: During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the relative contributions of mRNA transcription and degradation to shaping those profiles ... ...

Abstract	During embryonic development, pluripotent cells assume specialized identities by adopting particular gene expression profiles. However, systematically dissecting the relative contributions of mRNA transcription and degradation to shaping those profiles remains challenging, especially within embryos with diverse cellular identities. Here, we combine single-cell RNA-Seq and metabolic labeling to capture temporal cellular transcriptomes of zebrafish embryos where newly-transcribed (zygotic) and pre-existing (maternal) mRNA can be distinguished. We introduce kinetic models to quantify mRNA transcription and degradation rates within individual cell types during their specification. These models reveal highly varied regulatory rates across thousands of genes, coordinated transcription and destruction rates for many transcripts, and link differences in degradation to specific sequence elements. They also identify cell-type-specific differences in degradation, namely selective retention of maternal transcripts within primordial germ cells and enveloping layer cells, two of the earliest specified cell types. Our study provides a quantitative approach to study mRNA regulation during a dynamic spatio-temporal response.
MeSH term(s)	Animals ; Zebrafish ; Single-Cell Gene Expression Analysis ; Embryonic Development/genetics ; Transcription, Genetic ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Gene Expression Regulation, Developmental
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47290-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Identification of the Cryptic HLA-I Immunopeptidome.

Erhard, Florian / Dölken, Lars / Schilling, Bastian / Schlosser, Andreas

Cancer immunology research

2020 Volume 8, Issue 8, Page(s) 1018–1026

Abstract: The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often ... ...

Abstract	The success of cancer immunotherapy relies on the ability of cytotoxic T cells to specifically recognize and eliminate tumor cells based on peptides presented by HLA-I. Although the peptide epitopes that elicit the corresponding immune response often remain unidentified, it is generally assumed that neoantigens, due to tumor-specific mutations, are the most common targets. Here, we used a mass spectrometric approach to show an underappreciated class of epitopes that accounts for up to 15% of HLA-I peptides for certain HLA alleles in various tumors and patients. These peptides are translated from cryptic open reading frames in supposedly noncoding regions in the genome and are mostly unidentifiable with conventional computational analyses of mass spectrometry (MS) data. Our approach, Peptide-PRISM, identified thousands of such cryptic peptides in tumor immunopeptidomes. About 20% of these HLA-I peptides represented the C-terminus of the corresponding translation product, suggesting frequent proteasome-independent processing. Our data also revealed HLA-I allele-dependent presentation of cryptic peptides, with HLA-A03 and HLA-A11 presenting the highest percentage of cryptic peptides. Our analyses refute the reported frequent presentation of HLA peptides generated by proteasome-catalyzed peptide splicing. Thus, Peptide-PRISM represents an important step toward comprehensive identification of HLA-I immunopeptidomes and reveals cryptic peptides as an abundant class of epitopes with potential relevance for novel immunotherapeutic approaches.
MeSH term(s)	Algorithms ; Antigen Presentation/immunology ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/metabolism ; Computational Biology/methods ; Histocompatibility Antigens Class I/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Mass Spectrometry/methods ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; RNA, Untranslated/immunology ; T-Lymphocytes, Cytotoxic/immunology
Chemical Substances	Antigens, Neoplasm ; Histocompatibility Antigens Class I ; RNA, Untranslated
Language	English
Publishing date	2020-06-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-19-0886
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Article ; Online: An unusual mode of baseline translation adjusts cellular protein synthesis capacity to metabolic needs.

Schneider, Cornelius / Erhard, Florian / Binotti, Beyenech / Buchberger, Alexander / Vogel, Jörg / Fischer, Utz

Cell reports

2022 Volume 41, Issue 2, Page(s) 111467

Abstract: In all domains of life, mechanisms exist that adjust translational capacity to nutrient restriction and other growth constraints. The mammalian target of rapamycin (mTOR) regulates the synthesis of ribosomal proteins and translation factors in mammalian ... ...

Abstract	In all domains of life, mechanisms exist that adjust translational capacity to nutrient restriction and other growth constraints. The mammalian target of rapamycin (mTOR) regulates the synthesis of ribosomal proteins and translation factors in mammalian cells via phosphorylation of the La-related protein 1 (LARP1). In the present model of starvation-induced translational silencing, LARP1 targets mRNAs carrying a 5' terminal oligopyrimidine (5'TOP) motif to shift these into subpolysomal ribonucleoprotein particles. However, how these mRNAs would be protected from degradation and rapidly made available to restore translation capacity when needed remained enigmatic. Here, to address this, we employ gradient profiling by sequencing (Grad-seq) and monosome footprinting. Challenging the above model, we find that 5'TOP mRNAs, instead of being translationally silenced during starvation, undergo low baseline translation with reduced initiation rates. This mode of regulation ensures a stable 5'TOP mRNA population under starvation and allows fast reversibility of the translational repression.
MeSH term(s)	Protein Biosynthesis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Ribonucleoproteins/metabolism ; Ribosomal Proteins/metabolism ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	RNA, Messenger ; Ribonucleoproteins ; Ribosomal Proteins ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111467
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Article ; Online: Impaired T and "memory-like" NK-cell reconstitution is linked to late-onset HCMV reactivation after letermovir cessation.

Lauruschkat, Chris David / Muchsin, Ihsan / Rein, Alice Felicitas / Erhard, Florian / Grathwohl, Denise / Dölken, Lars / Köchel, Carolin / Nehmer, Anne / Falk, Christine S / Grigoleit, Götz Ulrich / Einsele, Hermann / Wurster, Sebastian / Kraus, Sabrina

Blood advances

2024

Abstract: Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens such as human cytomegalovirus (HCMV). Letermovir prophylaxis has ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation (alloSCT) is the only cure for many hematologic malignancies. However, alloSCT recipients are susceptible to opportunistic pathogens such as human cytomegalovirus (HCMV). Letermovir prophylaxis has revolutionized HCMV management, but the challenge of late HCMV reactivations has emerged. Immunological surrogates of clinically significant HCMV reactivations (csCMVi) after discontinuation of letermovir remain to be defined. Therefore, we studied NK-cell reconstitution along with the global and HCMV pp65-specific T-cell repertoire of 24 alloSCT recipients at seven timepoints before (day +90) and after (days +120-270) cessation of letermovir prophylaxis. Patients who experienced csCMVi had lower counts of IFNγ+ HCMV-specific CD4+ and CD8+ T cells than HCMV controllers. Furthermore, csCMVi patients displayed late impairment of NK-cell reconstitution, especially suppression of "memory-like" CD159c+CD56dim NK-cell counts that preceded csCMVi events in most patients. Moreover, several surrogates of immune reconstitution were associated with the severity of HCMV manifestation, with patients suffering from HCMV end-organ disease and/or refractory HCMV infection harboring least HCMV-specific T cells and "memory-like" NK cells. Altogether, our findings establish an association of delayed or insufficient proliferation of both HCMV-specific T cells and "memory-like" NK cells with csCMVi and the severity of HCMV manifestations following discontinuation of letermovir prophylaxis.
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023012008
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