Biology subjects

Le Noir, S.

Publications and source records attributed to Le Noir, S..

5 recordsLinked to original sources

bioRxiv2026

Lineage-specific regulation and RNA-associated functions of SATB1 in mature B-cells

Special AT-rich binding protein 1 (SATB1) is a nuclear matrix-associated transcription factor that orchestrates higher-order chromatin architecture and gene expression in T and B lymphocytes. While SATB1s role in T cells is well-established, its regulation and function in B cells remain underexplored. Here, we showed that Satb1 expression in mature B cells is controlled by alternative promoter usage and splicing, with promoters P1 and P3 dynamically switching upon LPS-induced activation, while P2 remains transcriptionally silent. We identified four Satb1 mRNA isoforms, including two novel transcripts ({Delta}9 and{Delta} 9{Delta}11), all of which maintain open reading frames. Satb1 transcription decreases upon activation while SATB1 protein content evolves differently, suggesting post-transcriptional regulation. SATB1 forms a high-molecular-weight complex in B cells, and co-immunoprecipitation mass spectrometry reveals RNA-binding proteins as its predominant interactors. These findings specify SATB1 expression kinetics during B-cell activation and reveal its role as a regulator of RNA splicing in B cells.

immunology↗

bioRxiv2023

Core enhancers of the 3'RR optimize IgH nuclear position and loop conformation for oriented CSR

Class switch recombination is an essential process which enabling B cells to adapt immunoglobulin subtypes to antigens. Transcription plays a crucial role in regulating CSR in which the IgH 3Regulatory Region (3RR) was identified as a key player. The 3RR stands at the 3 end of IgH locus and is composed of four core enhancers surrounded by inverted repeated sequences, forming a quasi-palindrome. In addition to transcriptional control, nuclear organization appears to be an important level in CSR regulation. Furthermore, the chromatin loops at IgH locus facilitate an efficient CSR recombination by bringing the donor and acceptor switch regions closer together. However, the precise control mechanisms governing both of these processes remain partially understood. Here, using the reference DNA 3D-FISH technique combined with various high throughput approaches, we showed that 3RR core enhancers are necessary and sufficient to preorganize resting B cell nuclei to facilitate a deletional CSR mechanism at activated stage. We demonstrated that the 3RR core enhancers regulate IgH locus addressing in the nuclei, control IgH locus accessibility and orchestrate IgH loops formation. Our findings pinpointed an additional regulation level of mechanisms underlying B cell diversification. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/548507v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@69ca5aorg.highwire.dtl.DTLVardef@1640c29org.highwire.dtl.DTLVardef@15a7949org.highwire.dtl.DTLVardef@d0af7e_HPS_FORMAT_FIGEXP M_FIG C_FIG Position of IgH loci through B cell development (from transitional to stimulated stages) is represented by the red spots. In wt and c3RR context, IgH loci get closer from each other and from nucleus center during evolution from transitional to mature resting stage and they relocates more at nuclear periphery, away one from each other, upon in vitro stimulation. In{Delta} 3RR model, this dynamic is lost and, moreover, IgH loci are more localized to pericentromeric heterochromatin (represented by green area) since the mature resting B cell stage and remain in after in vitro stimulation.

immunology↗

bioRxiv2022

A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells

SATB1 (Special A-T rich Binding protein 1) is a cell type specific factor involved in chromatin remodelling events that participate in the regulation of the genetic network in developing T cells and neurons. In T cells, SATB1 is a key factor required for lineage commitment, VDJ recombination, development and maturation. In B cells, SATB1 is described as binding to the MARs-E{micro} regions of the IgH locus. Considering that its expression varies during differentiation, the involvement of this factor needed to be clarified in B cells. Using a KO mouse model deleting SATB1 from the pro-B cell stage, we were able to examine the consequences of SATB1 deletion in naive and activated B cell subsets. Our model indicates firstly that SATB1 is not essential for B cell development and the establishment of a broad IgH repertoire. Second, we show that this factor exhibits an ambivalent function in mature B cells, acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells, respectively. Third, our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response in which this factor limits somatic hypermutation of Ig genes. This finding suggests that SATB1 may limit the introduction of unwanted mutations into B cells.

immunology↗

bioRxiv2022

The IgH Eμ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

Two scaffold/matrix attachment regions (5- and 3-MARsE) flank the intronic core enhancer (cE) within the immunoglobulin heavy chain locus (IgH). Besides their conservation in mice and humans, the physiological role of MARsE is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated. By analysing a mouse model devoid of MARsE, we observed an inverted substitution pattern: SHM being decreased upstream from cE and increased downstream of it. Strikingly, the SHM defect induced by MARsE-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from cE in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process. Our study pointed out an unexpected "fence" function of MARsE regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.

immunology↗

bioRxiv2021

Diverse B-cell specific transcriptional contexts of the BCL2 oncogene in mouse models impacts pre-malignant development

Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptotic BCL2 gene under the direct control of the transcriptional enhancers in 3 of immunoglobulin heavy chain locus (IgH 3RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the BCL2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Ig{kappa}-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3RR-BCL2 (Transgene containing BCL2 and a micro-3RR), both containing the full BCL2 promoter region.

immunology↗