Biology subjects

Sarrazin, S.

Publications and source records attributed to Sarrazin, S..

5 recordsLinked to original sources

bioRxiv2026

Stemness overcomes IFNγ-induced antitumour exhaustion in human macrophages

Macrophages hold great promise for antitumour therapies (1-4), particularly owing to their ability to infiltrate solid tumours (5). Yet therapeutic success has been limited (6,7), because macrophages exhibit rapid exhaustion of antitumorigenic activity in the tumour (5,8,9). Here, we induced a stem-like self-renewal programme in human induced pluripotent stem cell (iPSC)-derived macrophages by deleting the self-renewal restricting transcription factors MAFB and MAF (MAF-DKO). Human MAF-DKO macrophages showed activated stem cell signatures, increased clonogenicity and proliferative potential. Increased self-renewal capacity was accompanied by enhanced mitochondrial fitness and invigorated energy metabolism. Importantly, these stemness features prevented exhaustion, cellular aging-associated parameters and loss of energy efficiency that are typically associated with proinflammatory macrophage activation. In addition, activated MAF-DKO macrophages showed a broad loss of IFN{gamma}-triggered immunosuppressive pathways (10,11), induced a super-activated state with robust cytotoxic activity and resisted exhaustion upon tumour cell exposure. Consequently, activated MAF-DKO macrophages showed intratumoral persistence with a stable antitumoral phenotype in vivo, conferred robust reduction of tumour burden and extended survival of tumour-bearing mice. Together, this demonstrates that the induction of stemness in human macrophages can overcome critical roadblocks of antitumour therapy by conferring resistance to activation-triggered exhaustion of antitumour activity in the TME.

immunology↗

bioRxiv2024

Epromoters bind key stress-related transcription factors to regulate clusters of stress response genes

Stress insults trigger the rapid and global reprogramming of gene transcription by coordinated recruitment of a limited number of key inducible transcription factors to cis-regulatory elements. Here, we performed a comprehensive analysis of different stress models and observed that co-induced genes are generally located in close genomic proximity. By integrating gene expression and transcription factor binding resources in different stress models, we found an enrichment for clusters whereby only one of the promoters of the cluster recruits the key transcription factors, reminiscent of Epromoters, a type of cis-regulatory elements displaying both promoter and enhancer function. Epromoter-regulated clusters were frequently found irrespectively of the stress or inflammatory response. Predicted Epromoters displayed enhancer activity and regulated clusters of stress-response genes independently of their genomic location. These findings have significant implications for understanding complex gene regulation following the response to acute perturbations. TeaserWhen cells face stress, they undergo rapid changes in gene expression, orchestrated by a handful of key transcription factors. But how do these factors coordinate such a complex response? Our study reveals that "Epromoters"--cis-regulatory elements that combine the functions of both promoters and enhancers help organize stress-response genes into tightly regulated clusters. This discovery not only deepens our understanding of gene regulation in the face of stress but also offers exciting implications for studying inflammation and other acute cellular responses.

genomics↗

bioRxiv2023

MAFB drives differentiation by permitting WT1 binding to podocyte 1 specific promoters

Podocytes are highly specialized cells, but their chromatin status and the precise molecular events leading to their differentiation remain poorly defined. Here we used ChIP-Seq analysis for H3K4me3, H3K4me1 and H3K27me3 to establish the histone methylation map in adult mouse podocytes. Our data demonstrate open chromatin across podocyte specific genes and reveals that genes expressed in the mesoderm lineage become actively repressed upon podocyte differentiation. To better understand the transcriptional control of podocyte differentiation, we studied the role of transcription factor MAFB. ChIP-Seq experiments and functional analysis in conditional knockout mice identified a set of direct MAFB targets including Nphs1, Nphs2, Vegfa and Tcf21. Loss of MafB led to the deposition of extracellular matrix, progressive foot process effacement, and kidney disease. ChIP experiments in knockout animals revealed that during development MAFB is essential for H3K4me3 methylation and the recruitment of WT1 to the promoters of the podocyte specific genes Nphs1 and Nphs2. Taken together our data reveal the crucial function of MAFB by permitting chromatin accessibility at podocyte-specific genes during development and maintaining terminal differentiation in adults.

developmental biology↗

bioRxiv2023

M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation

Immunosuppressed patients are highly susceptible to viral infections. Therapies reconstituting autologous antiviral immunocompetence could therefore represent an important prophylaxis and treatment. Herpesviridae including cytomegalovirus (CMV) are a major cause of morbidity and mortality in patients after hematopoietic cell transplantation (HCT). Here, we show in a mouse model of HCT that macrophage colony-stimulating factor (M-CSF/CSF-1), a key cytokine for myeloid and monocytic differentiation, promoted rapid antiviral activity and protection from viremia caused by murine CMV. Mechanistically, M-CSF stimulated a coordinated myeloid and natural killer (NK) cell differentiation program culminating in increased NK cell numbers and production of granzyme B and interferon-{gamma}. This NK cell response depended upon M-CSF-induced myelopoiesis leading to IL15R-mediated presentation of IL-15 on monocytes. Furthermore, M-CSF also induced differentiation of plasmacytoid dendritic cells producing type I interferons, which supported IL-15-mediated protection. In the context of human HCT, M-CSF induced monopoiesis, increased IL15R expression on monocytes and elevated numbers of functionally competent NK cells in G-CSF-mobilized human hematopoietic stem and progenitor cells. Together, our data show that M-CSF induces an integrated multistep differentiation program that culminates in increased NK cell numbers and activation, thereby protecting graft recipients from CMV infection. Thus, our results identify a mechanism by which M-CSF-induced myelopoiesis can rapidly reconstitute antiviral activity during leukopenia following HCT. Key pointsO_LIM-CSF protects from lethal CMV viremia during leukopenia following hematopoietic cell transplantation, a vulnerable period of immunosuppression. C_LIO_LIEarly action of M-CSF on donor hematopoietic stem and progenitor cells rapidly reconstitutes antiviral immune responses. C_LIO_LIM-CSF stimulates a coordinated myeloid-NK cell-differentiation program resulting in increased NK cell numbers and activity. C_LIO_LIIncreased NK cell differentiation and activity depends on M-CSF-induced myelopoiesis generating IL-15-producing monocytes and I-IFN-producing pDCs. C_LIO_LIM-CSF also stimulates monopoiesis, IL15Ra expression in monocytes and functional NK cell differentiation in G-CSF-mobilized human PBMC. C_LIO_LINo impaired HCT engraftment or proclivity to graft-versus-host-disease by M-CSF. C_LIO_LIM-CSF could provide a single cytokine therapy addressing a major medical need, supporting current antiviral therapies during leukopenia following HCT. C_LI Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/526105v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1b1398eorg.highwire.dtl.DTLVardef@39a9e3org.highwire.dtl.DTLVardef@1c08cc3org.highwire.dtl.DTLVardef@5996b4_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryM-CSF drives myeloid reconstitution to support CMV-directed natural killer cell competence via IL-15/I-IFN after hematopoietic cell transplantation.

immunology↗

bioRxiv2018

Increased and decreased superficial white matter structural connectivity in schizophrenia and bipolar disorder

Schizophrenia (SZ) and bipolar disorder (BD) are often conceptualized as \"disconnection syndromes\", with substantial evidence of abnormalities in deep white matter tracts, forming the substrates of long-range connectivity, seen in both disorders. However, the study of superficial white matter (SWM) U-shaped short-range tracts remained challenging until recently, although findings from post-mortem studies suggest they are likely integral components of SZ and BD neuropathology. This diffusion weighted imaging (DWI) study aimed to investigate SWM microstructure in vivo in both SZ and BD for the first time. We performed whole brain tractography in 31 people with SZ, 32 people with BD and 54 controls using BrainVISA and Connectomist 2.0. Segmentation and labelling of SWM tracts were performed using a novel, comprehensive U-fiber atlas. Analysis of covariances yielded significant generalized fractional anisotropy (gFA) differences for 17 SWM bundles in frontal, parietal and temporal cortices. Post hoc analyses showed gFA reductions in both patient groups as compared with controls in bundles connecting regions involved in language processing, mood regulation, working memory and motor function (pars opercularis, insula, anterior cingulate, precentral gyrus). We also found increased gFA in SZ patients in areas overlapping the default mode network (inferior parietal, middle temporal, precuneus), supporting functional hyperconnectivity of this network evidenced in SZ. We thus illustrate that short U-fibers are vulnerable to the pathological processes in major psychiatric illnesses, encouraging improved understanding of their anatomy and function.

neuroscience↗