Biology subjects

Sigvardsson, M.

Publications and source records attributed to Sigvardsson, M..

6 recordsLinked to original sources

bioRxiv2026

GATA transcription factors act as gatekeepers between the Wnt/β-catenin-mediated proliferation and differentiation in the intestinal epithelium

Wnt/{beta}-catenin signalling drives gene expression in a plethora of processes during development and tissue homeostasis. Yet, little is known about how {beta}-catenin, the transducer of the pathway, gives rise to context-specific transcriptional outcomes. For example, in the intestinal epithelium, stem cells and secretory cells lie adjacent to each other, are both exposed to and dependent on Wnt signals, but display divergent identities. We find that, in this tissue, GATA transcription factors functionally interact with Wnt/{beta}-catenin signaling to drive differential cell identity. This occurs because GATA selectively repress Wnt target secretory-lineage genes in stem cells. Mechanistically, we found that GATA factors physically engage with the {beta}-catenin transcriptional complex, and that this association is mediated by the bridge protein BCL9/9L. Our work implicates GATA factors as context dependent modulators of the Wnt/{beta}-catenin transcription, shows that the GATA/BCL9 module acts as a switch at the crossroads of cell identity decision, and uncovers how this epithelium maintains the fine balance between self-renewal and differentiation.

developmental biology↗

bioRxiv2026

Multi-omic profiling of human antibody-secreting cells reveals diverse subsets sustain durable humoral immunity

Antibody-secreting cells (ASCs) provide humoral immunity that can mediate lifelong protection against pathogens. Current classifications cannot delineate the heterogenous functionalities, tissue residencies, and lifespans of human ASC subsets, impeding clinical translation. We applied multi-omic sequencing, spatial proteomics, and functional assays to discover and characterize human bone marrow (BM) ASC subsets. We identified two peripheral subsets (ASCp) also present in blood and three BM-resident subsets (ASCr), comprising a maturation continuum associated with increased mitochondrial networking, diminished antibody secretion, differential transcription factor motif accessibility, and preferential co-localization in homotypic niches. CD19+9+ASCr and CD19-ASCr exhibited poor recovery years after BM transplantation, indicating a strong dependence on supportive niches. Childhood vaccine antigens were recognized by long-lived ASCr subsets in adults and by immature HLA-DR+ASCp, implying ASCs can differentiate without recent antigen exposure. Our results provide new insights into ASC identity, maturation, and longevity and a generalizable framework for study and manipulation of human ASCs.

immunology↗

bioRxiv2025

Dissecting type I and II interferon impacts on human immune cells in disease by a cell type-specific interferon response atlas

Interferons (IFNs) orchestrate diverse immune responses, but distinguishing individual IFN contributions in human transcriptomic data is challenging due to overlapping interferon-stimulated gene (ISG) signatures and limited cell-type-specific datasets. To address this, we generated a single-cell transcriptomic atlas of IFN responses by stimulating primary human T, B, NK, and CD14 monocytes with IFN-I, IFN-II, and IFN-III. This revealed core and cell-type-specific ISG programs across 13 subsets, highlighting distinct functions of IFNs. We developed an algorithm to separate IFN-I and IFN-II activity in transcriptomic data. Applied to multiple myeloma samples, it showed elevated IFN-I and IFN-II responses, with induction therapy reducing only IFN-I. Extending to multiple disease datasets provided a cross-disease overview of IFN-I and IFN-II activities and revealed increased IFN-II activities in T cells during lupus flares. This resource and the accompanying analytical framework enable dissection of IFN-driven transcriptional programs in a cell-type specific manner in human disease.

immunology↗

bioRxiv2025

Chromatin interaction-based annotation of distal cis-regulatory elements reveals highly dynamic promoter-enhancer interactions in lymphocyte development

Stage- and lineage-specific gene expression patterns are controlled by a complex interplay between transcription factors, the epigenetic landscape, and the 3-dimensional (3D) structure of the DNA. The 3D structure allows for the formation of DNA loops that juxtaposition distal regulatory elements to the promoters, allowing for tight control of gene expression. These loops can span hundreds of thousands base pairs, making it challenging to link regulatory elements to the correct target genes using conventional proximity-based annotation methods. Using a novel tool to facilitate the exploration of complex gene regulatory networks based on chromosome configuration data in early lymphocytes, we show that lineage-specific transcription factors target regulatory elements that are annotated to both lineage-specific and broadly expressed genes. Targeted inactivation of a set of these genes revealed their importance for B-cell development. Several regulatory elements annotated to lineage-specific genes were also annotated to alternative promoters in a context dependent manner, revealing a highly complex interplay between promoters and DREs in early lymphocyte development. Investigating the chromatin configuration in EBF1 deficient pro-B cells identified this transcription factor as a key mediator in the establishment of the 3-D promoter enhancer landscape in early B-lymphocyte differentiation. These data highlight how efficient annotation procedures for linking distal regulatory elements to target genes provide valuable insights into gene regulatory networks.

bioinformatics↗

bioRxiv2022

TGF-β promotes the postselection thymic development and peripheral function of interferon-γ-producing iNKT cells

Interferon-{gamma} producing invariant natural killer T (iNKT1) cells are lipid reactive innate-like lymphocytes that are resident in the thymus and peripheral tissues where they protect against pathogenic infection. The thymic functions of iNKT1 cells are not fully elucidated but subsets of thymic iNKT cells modulate CD8 T cell, dendritic cell, B cell and thymic epithelial cell numbers or function. Here we show that a subset of thymic iNKT1 cells require transforming growth factor (TGF)-{beta} induced signals for their development and for expression of residency associated adhesion receptors. Liver and spleen iNKT1 cells do not share this TGF-{beta} gene signature but nonetheless TGF-{beta} is required for optimal liver iNKT1 cell function. Our findings provide insight into the heterogeneity of mechanisms guiding iNKT1 cell development in different tissues and suggest a close association between a subset of iNKT1 cells and TGF-{beta} producing cells in the thymus.

immunology↗

bioRxiv2018

Pioneering, chromatin remodeling, and epigenetic constraint in early T-cell gene regulation by PU.1

PU.1 is a dominant but transient regulator in early T-cell precursors and a potent transcriptional controller of developmentally important pro-T cell genes. Before T-lineage commitment, open chromatin is frequently occupied by PU.1, and many PU.1 sites lose accessibility when PU.1 is later downregulated. Pioneering activity of PU.1 was tested in in this developmentally dynamic context, by quantitating the relationships between PU.1 occupancy and site quality and accessibility as PU.1 levels naturally declined in pro-T cell development, and by using stage-specific gain and loss of function perturbations to relate binding to effects on target genes. PU.1 could bind closed genomic sites, but rapidly opened many of them, despite the absence of its frequent collaborators, C/EBP factors. The dynamic properties of PU.1 engagements implied that PU.1 binding affinity and concentration determine its occupancy choices, but with quantitative tradeoffs for occupancy between site sequence quality and stage-dependent site accessibility in chromatin. At non-promoter sites PU.1 binding criteria were more stringent than at promoters, and PU.1 was also much more effective as a transcriptional regulator at non-promoter sites where local chromatin accessibility depended on the presence of PU.1. Runx motifs and Runx1 binding were often linked to PU.1 at open sites, but highly expressed PU.1 could bind its sites without Runx1. Notably, closed chromatin presented a qualitative barrier to occupancy by the PU.1 DNA binding domain alone. Thus, effective pioneering at closed chromatin sites also depends on requirements beyond site recognition served by non-DNA binding domains of PU.1.

immunology↗