Biology subjects

Chopin, M.

Publications and source records attributed to Chopin, M..

5 recordsLinked to original sources

bioRxiv2025

SATB1 maintains naive-like identity in antiviral CD8⁺ T cells by limiting chromatin remodelling at effector gene loci.

Optimal CD8+ T cell differentiation requires the engagement of transcriptional programs that drive effector phenotypes and function, whilst also shutting down transcriptional programs that maintain the naive state. While the distinct factors that underpin each state are well studied, the molecular mechanisms that control the switch from the naive to effector state are not fully understood. Utilising integrated analysis of single-cell genomic data, we identified CD8+ T cell effector transcriptional networks that are restrained in the naive state by the chromatin binding protein Special AT-rich sequence binding protein-1 (SATB1). Utilising a SATB1-Tg model, whereby activated CD8+ T cells are unable to down regulate SATB1 upon activation, we observed limited effector differentiation and an inability to engage effector programs in response to both primary and secondary influenza A virus infection. Mechanistically, SATB1 limited chromatin remodelling at key gene loci required for the full engagement of the CD8+ T cell effector program. Hence, SATB1 is a master gatekeeper that maintains the naive T cell state and whose downregulation is necessary to allow transition from a naive to effector state upon T cell activation. SATB1 modulation may provide new strategies for improving CD8+ T cell longevity and self-renewal capacity in different immunotherapeutic treatments.

immunology↗

bioRxiv2024

Transcriptional Regulatory Logic Orchestrating Lymphoid and Myeloid Cell Fate Decisions

The differentiation of hematopoietic stem cells (HSCs) into diverse blood and immune cells is a complex, highly hierarchical process characterized by a series of tightly regulated steps. It involves a sequence of intermediate oligo-potent progenitors making successive binary decisions. This process gradually narrows down lineage possibilities until a final fate is reached. This step-wise process is tightly controlled by Transcription Factors (TFs) and their associated regulome ultimately resulting the differentiation of both lymphoid and myeloid compartments. Here, we set to unravel the lineage-specific gene regulatory circuitry controlling the development of B cells, T cells, Innate Lymphoid Cells (ILCs), and Dendritic Cells (DCs). We employ Weighted Gene Co-expression Network Analysis (WGCNA) to characterize gene modules associated to the lymphoid or myeloid cell fate, enabling the identification of lineage restricted TFs based on their expression patterns. By identifying TFs whose expression is subset-restricted or those with a broader expression in the hematopoietic compartment we construct a regulatory logic that potentially controls the development of these key immune cells. Our results point to conserved regulatory elements between ILCs, Natural Killer cells, and DCs. This analysis unravels an intricate relationship between each cell types and how the expression of key TFs dictate lineage specificity. We particularly dissect the elements associated to conventional DCs and plasmacytoid DCs. In conclusion, our findings shed new lights on regulatory mechanisms controlling blood cell development and offer a blueprint that can be leveraged to better understand the molecular mechanisms underpinning blood cell development.

cell biology↗

bioRxiv2024

BATF controls IFN I production via DC-SCRIPT in plasmacytoid dendritic cells

The basic leucine zipper ATF-like transcription factor (BATF) plays a pivotal role in coordinating various aspects of lymphoid cell biology, yet essential functions in dendritic cells (DCs) have not been reported. Here we demonstrate that BATF deficiency leads to increased interferon (IFN) I production in Toll-like receptor 9 (TLR9)-activated plasmacytoid dendritic cells (pDCs), while BATF overexpression has an inhibitory effect. BATF-deficient mice exhibit elevated IFN I serum levels early in lymphocytic choriomeningitis virus (LCMV) infection. Through ATAC-Seq analysis, BATF emerges as a pioneer transcription factor, regulating approximately one third of the known transcription factors in pDCs. Integrated transcriptomics and ChIP-Seq approaches identified the transcriptional regulator DC-SCRIPT as a direct target of BATF that suppresses IFN I promoter activity by interacting with the interferon regulatory factor 7 (IRF7). Genome-wide association study (GWAS) analyses further implicate BATF in pDC-mediated human diseases. Our findings establish a novel negative feedback axis in IFN I regulation in pDCs during anti-viral immune responses orchestrated by BATF and DC-SCRIPT, with broader implications for pDC and IFN I-mediated autoimmunity.

immunology↗

bioRxiv2022

CIS calibrates GM-CSF signalling strength to regulate macrophage polarization via a STAT5-IRF8 axis

The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the ability to differentiate macrophages (MOs) with opposing functions, namely proinflammatory M1-like and immunosuppressive M2-like. Despite the importance and opposing functional outcomes of these processes, the intrinsic mechanism that regulates the functional polarization of MOs under GM-CSF signaling remains elusive. Here we show that GM-CSF induced MOs polarisation resulted in the expression of the Cytokine-inducible SH2-containing protein (CIS), and that CIS deficiency diverted differentiation of monocytes into immunosuppressive M2-like MOs expression. CIS deficiency resulted in the hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting the downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss and gain of function approaches highlighted IRF8 as a critical instructor of the M1-like polarisation program. In vivo, CIS deficiency led to skewing to M2-like macrophages, which induced strong Th2 immune responses characterised by the development of severe experimental asthma. Collectively, we reveal a CIS-censored mechanism interpreting the opposing actions of GM-CSF in MO differentiation and uncovering its role in controlling allergic inflammation.

immunology↗

bioRxiv2021

EHF is essential for epidermal and colonic epithelial homeostasis and suppresses Apc-initiated colonic tumorigenesis

BackgroundEts homologous factor (EHF) is a member of the epithelial-specific Ets (ESE) transcription factors. EHF is specifically expressed in epithelial tissues, however its role in development and epithelial homeostasis is largely uncharacterized. MethodsWe generated a novel mouse strain in which the Ets DNA binding domain (exon 8) of Ehf was flanked by loxP sites (EhfLox/Lox). To inactivate Ehf in the whole body, EhfLox/Lox mice were crossed to CMVCre mice, which were then bred out to generate germline Ehf null (Ehf-/-) mice. To inactivate Ehf specifically in the intestinal epithelium, EhfLox/Lox mice were bred to tamoxifen-inducible VillinCre-ERT2 mice. EhfLox/Lox mice were also crossed to tamoxifen-inducible Cdx2CreERT2; ApcLox/+ mice to determine the impact of Ehf deletion on Apc-initiated colon cancer development. ResultsTranscripts encoding the Ets binding domain of EHF were effectively deleted in all tissues in Ehf-/- mice. Ehf-/- mice were born at the expected Mendelian ratio, but showed reduced body weight gain and developed a series of pathologies during their lifespan that led the majority of Ehf-/- mice to reach an ethical endpoint within one year of age. Most prominent of these were the development of papillomas in the chin, and abscesses in the preputial glands (males) or vulvae (females) which showed evidence of Staphylococcus and Proteus infection. Consistent with the development of papillomas, the epidermis of Ehf-/- mice showed evidence of mild hyperplasia. A subset of Ehf-/- mice also developed cataracts and corneal ulcers. EHF is highly expressed in the colonic epithelium and Ehf-/- mice displayed increased susceptibility to dextran sodium sulphate-induced colitis. This phenotype was confirmed in intestinal-specific Ehf knockout mice, and histopathological analyses revealed reduced numbers of goblet cells and extensive transcriptional reprogramming in the colonic epithelium. Finally, colon-specific deletion of Ehf enhanced Apc-initiated adenoma development, unveiling a novel, tumour suppressive role for EHF in colorectal cancer. ConclusionThe Ets DNA-binding domain of EHF is essential for post-natal homeostasis of the epidermis and colonic epithelium, and functions as a tumour suppressor in the colon.

cell biology↗