Biology subjects

Dermadi, D.

Publications and source records attributed to Dermadi, D..

7 recordsLinked to original sources

bioRxiv2022

Imputing abundances and inferring direction of associations between histone modifications using neural processes

Histone post-translational modifications (HPTMs) play a vital role in the regulation of numerous cellular processes. However, systems level understanding of how HPTMs coordinate and interact with each other, and the direction of interactions remain unexplored due to lack of suitable technology. EpiTOF, a high-dimensional mass cytometrybased platform, measures HPTMs and histone variants across multiple immune cell sub-types at a single-cell resolution to enable the system-wide study of HPTMs. Large number of immune cells profiled using EpiTOF present an unprecedented opportunity to learn directional networks of HPTM associations. We developed a two-step computational framework to identify direction of association between two HPTMs. In the first step, we used linear regression (LR)-, k-nearest neighbors-(kNN), or Neural Processes (NP)-based to impute the abundance of HPTMs. In the second step, we developed an interpretation framework to infer direction of association between HPTMs at a system-level using mass cytometry data. We evaluated this framework using EpiTOF profiles of more than 55 million peripheral mononuclear blood cells from 158 healthy human subjects. NP models had consistently higher imputation accuracy than LR and kNN. The inferred networks recapitulated known HPTM associations and identified several novel ones. While almost all associations were conserved across all healthy individuals, in a cohort of healthy subjects, vaccinated with the trivalent inactivated seasonal influenza vaccine (TIV), we identified changes in associations between 6 pairs of HPTMs 30 days following vaccination, many of which have been shown to be functionally involved in innate memory. These results demonstrate utility of our framework in identifying causal interactions between HPTMs that can be further tested experimentally.

bioinformatics↗

bioRxiv2022

Crosstalk of Histone Modifications in the Healthy Human Immune System

Chromatin remodeling through post-translational modifications of histone tails (HPTM) is fundamental for regulation and maintenance of DNA-centered processes. Systems level understanding of coordination and interactions between HPTMs and their impact on the functional state of the immune cells remain unexplored due to the technical reasons. We leveraged large biologically heterogeneous data (>27 million cells), comprising of primary human immune cells profiled for 33 HPTMs and 4 histone variants at the single-cell level using high-dimensional mass cytometry (EpiTOF), to discover and map relations between HPTMs at the systems level. Briefly, we elucidated a comprehensive epigenetic network of HPTM interactions, discovered a novel subset of hematopoietic progenitors with distinct epigenetic profile, and revealed hitherto undescribed associations between a decrease in global methylations, modulation of one-carbon metabolism, and immune cell life span. Ultimately our work lays a foundation for future studies aimed at understanding complexity of HPTM interactions in immune response in infectious or autoimmune diseases, cancers, and vaccination.

immunology↗

bioRxiv2022

Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases

Current concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.

physiology↗

bioRxiv2020

A molecular map of lymph node blood vascular endothelium at single cell resolution

Blood vascular endothelial cells (BECs) control the immune response by regulating immune cell recruitment, metabolite exchange and blood flow in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain poorly understood. Here we profile transcriptomes of BEC from mouse peripheral lymph nodes and map key phenotypes to the vasculature. Our analysis identifies multiple novel subsets including a venous population whose gene signature predicts an unexpectedly selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by 2 photon videomicroscopy. We define five phenotypes of capillary lining BEC including a capillary resident regenerative population (CRP) that displays stem cell and migratory gene signatures and contributes to homeostatic BEC turnover and to vascular neogenesis after immunization. Trajectory analyses reveal retention of developmental programs along a progression of cellular phenotypes from CRP to mature venous and arterial BEC subsets. Overall, our single cell atlas provides a molecular blueprint of the lymph node blood vasculature and defines subset specialization for immune cell recruitment and vascular homeostasis.

immunology↗

bioRxiv2020

A single-cell transcriptional roadmap of the mouse and human lymph node lymphatic vasculature

Single-cell transcriptomics promises to revolutionize our understanding of the vasculature. Emerging computational methods applied to high dimensional single cell data allow integration of results between samples and species, and illuminate the diversity and underlying developmental and architectural organization of cell populations. Here, we illustrate these methods in analysis of mouse lymph node (LN) lymphatic endothelial cells (LEC) at single cell resolution. Clustering identifies five well-delineated subsets, including two medullary sinus subsets not recognized previously as distinct. Nearest neighbor alignments in trajectory space position the major subsets in a sequence that recapitulates known and suggests novel features of LN lymphatic organization, providing a transcriptional map of the lymphatic endothelial niches and of the transitions between them. Differences in gene expression reveal specialized programs for (1) subcapsular ceiling endothelial interactions with the capsule connective tissue and cells, (2) subcapsular floor regulation of lymph borne cell entry into the LN parenchyma and antigen presentation, and (3) medullary subset specialization for pathogen interactions and LN remodeling. LEC of the subcapsular sinus floor and medulla, which represent major sites of cell entry and exit from the LN parenchyma respectively, respond robustly to oxazolone inflammation challenge with enriched signaling pathways that converge on both innate and adaptive immune responses. Integration of mouse and human single-cell profiles reveals a conserved cross-species pattern of lymphatic vascular niches and gene expression, as well as specialized human subsets and genes unique to each species. The examples provided demonstrate the power of single-cell analysis in elucidating endothelial cell heterogeneity, vascular organization and endothelial cell responses. We discuss the findings from the perspective of LEC functions in relation to niche formations in the unique stromal and highly immunological environment of the LN. Highlights Computational alignments ("trajectories") predict LN LEC organization in situ, revealing a continuum of phenotypes punctuated by specialized clusters Multiple intermediate phenotypes suggest LEC malleability Gene profiles define niche-specific functional specialization Medullary sinus LECs are comprised of Ptx3-LECs and Marco-LECs O_LIDistinct mechanisms for pathogen interactions and matrix modeling C_LIO_LIPtx3-LECs: paracortical and central medullary sinuses near hilus; enriched for genes driving lymphangiogenic responses and lymphocyte egress C_LIO_LIMarco-LECs: peri-follicular medullary sinuses; macrophage-associated genes, complement and coagulation cascade C_LI Niche-specific responses to inflammation O_LIIFN gene responses in SCS floor and medullary sinus LECs C_LIO_LISuppression of LEC identity genes in responding subsets C_LI Conserved and unique LEC subsets and gene programs across species O_LICore subsets common to mouse and human C_LIO_LIGreater diversity of subsets and intermediates in human LN LECs C_LI

systems biology↗

bioRxiv2019

Single-cell sequencing of mouse thymocytes reveals mutational landscape shaped by replication errors, mismatch repair and H3K36me3

BackgroundDNA mismatch repair (MMR) safeguards genome stability by correcting errors made during DNA replication. In vitro evidence indicates that the MMR machinery is recruited to chromatin via H3K36me3, a histone mark enriched in 3 exons of genes and associated with transcriptional activity. To dissect how replication errors, abundance of H3K36me3 and MMR together shape the mutational landscape in normal mammalian cells, we applied single-cell exome sequencing to thymic T cells isolated from MMR-proficient (Mlh1+/+) and MMR-deficient (Mlh1-/-) mice.\n\nResultsUsing single-cell exome sequencing we identified short deletions as sensitive and quantifiable reporters of MMR-dependent mutations. We found H3K36me3-enriched Huwe1 and Mcm7 genes to be mutational hotspots exclusive to Mlh1-/- T cells. In Mlh1+/+ cells, exons of H3K36me3-enriched genes had a lower mutation frequency compared to H3K36me3-depleted genes. Moreover, within transcriptionally active genes, 3 exons, often H3K36me3-enriched, rather than 5 exons had significantly fewer MMR-dependent mutations, indicating that MMR operates more efficiently within 3 exons in Mlh1+/+ T cells.\n\nConclusionsOur results provide evidence that H3K36me3 confers preferential MMR-mediated protection from transcription-associated deleterious replication errors. This offers an attractive concept of thrifty MMR targeting, where genes critical for the development of given cell type are preferentially shielded from de novo mutations by H3K36me3-guided MMR.

genomics↗

bioRxiv2018

Branching developmental pathways through high dimensional single cell analysis in trajectory space

High-dimensional single cell profiling coupled with computational modeling is emerging as a powerful means to elucidate developmental sequences and define genetic programs directing cell lineages. Here we introduce tSpace, an algorithm based on the concept of \"trajectory space\", in which cells are defined by their distance along nearest neighbor pathways to every other cell in a population. tSpace outputs a dense matrix of cell-to-cell distances that quantitatively reflect the extent of phenotypic change along developmental paths (developmental distances). Graphical mapping of cells in trajectory space allows unsupervised reconstruction and straightforward exploration of complex developmental sequences. tSpace is robust, scalable, and implements a global approach that attempts to preserve both local and distant relationships in developmental pathways. Applied to high dimensional flow and mass cytometry data, the method faithfully reconstructs known pathways of thymic T cell development and provides novel insights into regulation of tonsillar B cell development and trafficking. Applied to single cell transcriptomic data, the method unfolds complex developmental sequences, recapitulates pathways leading from intestinal stem cells to specialized epithelial phenotypes more faithfully than existing algorithms, and reveals genetic programs that correlate with fate decisions. tSpace profiling of complex populations in high-dimensional trajectory space is well suited for hypothesis generation in developing cell systems.

bioinformatics↗