Biology subjects

Mattoo, H.

Publications and source records attributed to Mattoo, H..

8 recordsLinked to original sources

bioRxiv2025

Finetuning Foundation Models for Temporal Clinical Transcriptomics Data

BackgroundTimeseries clinical transcriptomic datasets offer the opportunity to gain insights into the dynamics of disease mechanisms/treatment responses. However, their utility in uncovering temporal patterns is often limited by high noise levels and small sample sizes. Leveraging foundational gene embeddings and incorporating interaction information can help address these challenges, improve gene network analysis, and enable the detection of subtle changes that drive disease progression or drug response. ResultsWe finetuned gene embeddings from foundation models using healthy tissue gene expression data and used them in temporal GNNs to model gene expression of responder and non-responders to treatment in 3 disease datasets - ulcerative colitis, Crohns disease and psoriasis. Application of our method to these datasets confirmed known mechanisms associated with drug action, and also identified key differences between activated and repressed pathways for responders and non responders including B-Cell activation and mitochondria related activity in ulcerative colitis patients. ConclusionFinetuning gene embeddings from foundation models provide a richer context to model gene expression data compared to using them in their naive state. Even with smaller sample sizes, results from GNN-based temporal models outperform traditional methods by detecting known mechanisms of response and unraveling role of genes and mechanisms not known to be associated with response and non-response. Code AvailabilityCode and data are available in a public GitHub repository - https://github.com/Sanofi-Public/GNN-Timeseries

bioinformatics↗

bioRxiv2025

A unified network systems approach uncovers a core novel program underlying T follicular helper cell differentiation

T follicular helper (Tfh) cells are central to the adaptive immune response and exhibit remarkable functional diversity and plasticity. The complex nature of Tfh cell populations, inconsistent findings across experimental systems and potential differences across species have fueled ongoing debate regarding core regulatory pathways that govern Tfh differentiation. Many studies have experimentally investigated individual proteins and circuits involved in Tfh differentiation in limited contexts, each providing only a partial understanding of the process. To address this, we adopted a novel multi-scale network systems approach that incorporates both regulatory and protein-protein interactions. Our approach integrates diverse data types, captures regulation across multiple levels of immune system organization, and recapitulates known drivers. Further, we discover a core Tfh gene set that is conserved across tissue types and disease contexts, and is consistent across data modalities - bulk, single-cell and spatial. While components of this set have been individually reported, a novel aspect of our work lies in the discovery, characterization, and connectivity of this core signature using a single unbiased approach. Using this method, we also uncover a novel function of IL-12, a molecule with reported conflicting functions, in the regulation of Tfh differentiation. Notably, we find that, in both humans and mice, IL-12 is permissive for the differentiation of Tfh precursors, but blocks subsequent differentiation into GC Tfh cells. Overall, this work elucidates novel networks with unexplored roles in governing Tfh cell differentiation across species and tissues, paving the way for novel -therapeutic interventions.

immunology↗

bioRxiv2023

Comparative Analysis of Association Networks Using Single-Cell RNA Sequencing Data Reveals Perturbation-Relevant Gene Signatures

Single-cell RNA sequencing (scRNA-seq) data has elevated our understanding of systemic perturbations to organismal physiology at the individual cell level. However, despite the rich information content of scRNA-seq data, the relevance of genes to a perturbation is still commonly assessed through differential expression analysis. This approach provides a one-dimensional perspective of the transcriptomic landscape, risking the oversight of tightly controlled genes characterized by modest changes in expression but with profound downstream effects. We present GENIX (Gene Expression Network Importance eXamination), a novel platform for constructing gene association networks, equipped with an innovative network-based comparative model to uncover condition-relevant genes. To demonstrate the effectiveness of GENIX, we analyze influenza vaccine-induced immune responses in peripheral blood mononuclear cells (PBMCs) collected from recovered COVID-19 patients, shedding light on the mechanistic underpinnings of gender differences. Our methodology offers a promising avenue to identify genes relevant to perturbation responses in biological systems, expanding the scope of response signature discovery beyond differential gene expression analysis. HIGHLIGHTSO_LIConventional methods used to identify perturbation-relevant genes in scRNA-seq data rely on differential expression analysis, susceptible to overlooking essential genes. C_LIO_LIGENIX leverages cell-type-specific inferred gene association networks to identify condition-relevant genes and gene programs, irrespective of their specific expression alterations. C_LIO_LIGENIX provides insight into the gene-regulatory response to the influenza vaccine in naive and recovered COVID-19 patients, expanding on previously observed gender-specific differences. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/556872v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1837d3eorg.highwire.dtl.DTLVardef@1937860org.highwire.dtl.DTLVardef@c40114org.highwire.dtl.DTLVardef@22d3b9_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2022

GM-CSF-activated human dendritic cells promote type1 T follicular helper cells (Tfh1) polarization in a CD40-dependent manner

T follicular helper (Tfh) cells are specialized CD4+ T cells that regulate humoral immunity by providing B cell help. Tfh1 sub-population was recently identified and associated with severity in infection and autoimmune diseases. The cellular and molecular requirements to induce human Tfh1 differentiation are unknown. Our work investigated the role of human dendritic cells (DC) in promoting Tfh1 differentiation and their physiopathological implication in mycobacterium tuberculosis and mild COVID-19 infection. Activated human blood CD1c+ DC were cocultured with allogeneic naive CD4+ T cells. Single-cell RNA sequencing was then used alongside protein validation to define the induced Tfh lineage. DC signature and correlation with Tfh1 cells in infected patients was established through bioinformatic analysis. Our results show that GM-CSF-activated DC drove the differentiation of Tfh1 cells, displaying typical Tfh molecular features, including 1) high levels of PD-1, CXCR5, and ICOS expression; 2) BCL6 and TBET co-expression; 3) IL-21 and IFN-{gamma} secretion. Mechanistically, GM-CSF triggered the emergence of two distinct DC sub-populations defined by their differential expression of CD40 and ICOS-ligand (ICOS-L), and distinct phenotype, morphology, transcriptomic signature, and function. We showed that Tfh1 differentiation was efficiently and specifically induced by CD40highICOS-Llow DC in a CD40-dependent manner. Tfh1 cells were positively associated with a CD40highICOS-LLow DC signature in patients with latent mycobacterium tuberculosis and mild COVID-19 infection. Our study uncovers a novel CD40-dependent human Tfh1 axis. Immunotherapy modulation of Tfh1 activity might contribute to control diseases where Tfh1 are known to play a key role, such as infections. Significance StatementDendritic cells (DC) play a central role in triggering the adaptive immune response due to their T cell priming functions. Among different T cell subsets, it is still not clear how human type1 T follicular helper cells (Tfh1) differentiate. Tfh1 cells are implicated in several physiopathological conditions, including infections. Here we show that GM-CSF induces diversification of human DC. Only CD40highICOS-LLow DC were able to drive Tfh1 cell differentiation. We found that CD40highICOS-LLow DC signature was associated to Tfh1 cells in mycobacterium tuberculosis and COVID-19 patients. Our data reveal a previously undescribed pathway leading to human Tfh1 cell differentiation and highlight the importance of GM-CSF and CD40 as potential targets for the design of anti-infective therapies.

immunology↗

bioRxiv2021

Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation

T follicular helper (Tfh) cells play a critical role in T-dependent humoral immune responses. While genetic programs controlling Tfh cell differentiation have been extensively studied using murine models, studies in humans have been hampered by the lack of a robust in vitro differentiation system for Tfh cells. We characterized epigenomic landscapes across stages of Tfh cell differentiation in a healthy human tonsil using ATAC-Seq and CUT&RUN for selected histone modifications. We combined these epigenomic datasets and integrated them with the reference human protein interactome using a novel network propagation approach. Our approach uncovered subnetworks integral to Tfh cell differentiation. These subnetworks captured known Tfh cell drivers to a greater extent than conventional gene-centric analyses would, and also revealed novel modules that may be required for Tfh cell differentiation. We find that human Tfh cell subnetworks are functionally associated with specific immune signaling cascades including cytokine receptor driven pathways. Analyses of transcriptomic data revealed that in addition to these immune pathways being significantly dysregulated in severe COVID-19, the corresponding Tfh cell subnetworks are also transcriptionally perturbed to a similar extent. This provides a molecular mechanistic basis for the previously observed impaired Tfh cell differentiation and loss of germinal centers in severe COVID-19.

immunology↗

bioRxiv2020

B1 and B2 B cells are characterized by distinct CpG modification states at DNMT3A-maintained enhancers

We show that DNA methylation is a layered process in B lymphocytes. An underlying foundational methylome is stably established during B lineage commitment and overlaid with a DNMT3A-maintained dynamic methylome which is sculpted in distinct ways in B1 and B2 B cells during B cell development. An engineered loss of DNMT3A after commitment to the B lineage unmasks a foundational methylome that is shared in both B1 and B2 sub-lineages. The dynamic methylome is comprised of novel enhancers whose methylation state is maintained by DNMT3A but can be modulated in strikingly different ways in B1 and B2 B cells. During B1 B cell development, the dynamic methylome undergoes a prominent programmed demethylation event that is not observed during B2 B cell development. The methylation pattern of the dynamic methylome is determined by the coincident recruitment of DNMT3A and TET enzymes and it regulates the developmental expression of B1 and B2 lineage-specific genes.

immunology↗

bioRxiv2018

Alterations in sialic-acid O-acetylation glycoforms during murine erythrocyte development

9-O-acetylation of sialic acid is a common modification that plays important roles in host-pathogen interactions. CASD1 has been described as a sialate-O-acetyltransferase and has been shown to be essential for 9-O-acetylation of sialic acid in some cell lines in vitro. In this study, we used knockout mice to confirm that CASD1 is indeed responsible for 9-O-acetylation of sialic acids in vivo. We observed a complete loss of 9-O-acetylation of sialic acids on the surface of myeloid, erythroid and CD4+ T cells in Casd1-deficient mice. Although 9-O-acetylation of sialic acids on multiple hematopoietic lineages was lost, there were no obvious defects in hematopoiesis. Interestingly, red blood cells from Casd1-deficient mice also lost reactivity to TER-119, a rat monoclonal antibody that is widely used to mark the murine erythroid lineage. The sialic acid glyco-epitope recognized by TER-119 on red blood cells was sensitive to the sialic acid O-acetyl esterase activity of the hemagglutinin esterase from bovine coronavirus but not to the corresponding enzyme from the influenza C virus. During erythrocyte development TER-119+ Ery-A and Ery-B cells could be stained by catalytically inactive bovine coronavirus hemaggutinin-esterase but not by the inactive influenza C hemagglutinin esterase, while TER-119+ Ery-C stage cells and mature erythrocytes were recognized by both virolectins. These results suggest that throughout murine erythrocyte development, cells of the erythroid lineage express a glycoconjugate bearing a modified 7,9-di-O-acetyl form of sialic acid, that is recognized specifically by the bovine coronavirus lectin and not by the influenza C hemagglutinin, and this modified sialic acid moiety is a component of the TER-119 epitope. As erythrocytes mature, the surface of Ery-C cells and mature erythrocytes also acquires a distinct CASD1-dependent 9-O-acetyl sialic acid moiety that can be recognized by virolectins from both influenza C and bovine coronavirus that are specific for 9-O-acetyl sialic acid.

immunology↗

bioRxiv2018

The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo

Distinct TFH subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary and tertiary lymphoid organs has not been hitherto demonstrated. IL-4 expressing TFH cells are surprisingly sparse in human secondary lymphoid organs. In sharp contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and secondary lymphoid organs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4 secreting TFH cells differ both from PD1hi TFH cells that do not secrete IL-4 and IL4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjogrens syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells as well as of CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFH sub-population in human tertiary and secondary lymphoid organs that is linked to IgG4 class switching.

immunology↗