Biology subjects

Forne, T.

Publications and source records attributed to Forne, T..

4 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↗

bioRxiv2026

Genomic imprinting of the metabolic regulator gene Klf14 is regulated by a paternal sub-TAD anchored at Mest and a shared enhancer in mice.

KLF14 acts as a master regulator of gene expression in adipose tissue and variants at the human KLF14 gene show strong and reproducible association with type 2 diabetes and metabolic syndrome. Risk alleles are only pathologic when maternally inherited, consistent with the observation that KLF14/Klf14 is a maternally-expressed imprinted gene in human and mouse. However, how genomic imprinting is regulated at this important locus is currently unknown. In both species, KLF14/Klf14 is located [~]200 kb away from the paternally imprinted gene MEST/Mest, which is regulated by a maternal gametic differentially methylated region (gDMR) at its CpG island (CGI) promoter. Although the Klf14 CGI is kept unmethylated in most tissues, maternally-inherited DNA methylation (DNAme) marks are paradoxically required for Klf14 expression in mouse. Here, we show that Mest and Klf14 reside within the same topologically associating domain (TAD) in both mouse embryonic stem cells (ESCs) and differentiated cells, defined by sites of biallelic CTCF binding at the boundaries. Using allele-specific 4C-seq in F1 hybrid ESCs, we show that CTCF binding specifically to the unmethylated Mest gDMR generates a paternal allele-specific sub-TAD encompassing Klf14. We further show through CRISPR-Cas9-mediated mutagenesis, that deletions of the paternal Mest promoter region in ESCs as well as in vivo in mutant mice, results in both loss of Mest expression and acquisition of biallelic expression at Klf14. By analyzing epigenetic marks and chromatin looping in the Klf14-expressing pituitary cell line AtT-20, we identify a putative enhancer element shared by Mest and Klf14, providing a mechanistic model for the regulation of Klf14 imprinting. This work defines a new role for the Mest maternally methylated gDMR, revealing that it exerts long-range effects via allele-specific modulation of TAD structures and consequently act as an imprinting control region (ICR) in the regulation of Klf14 imprinting. Conservation of this TAD organisation at the human locus suggests that a similar regulatory mechanism operates at KLF14.

developmental biology↗

bioRxiv2022

SUMOylation controls the rapid transcriptional reprogramming induced by anthracyclines in Acute Myeloid Leukemias

Genotoxicants have been used for decades as front-line therapies against cancer on the basis of their DNA-damaging actions. However, some of their non-DNA-damaging effects are also instrumental for killing dividing cells. We report here that the anthracycline Daunorubicin (DNR), one of the main drugs used to treat Acute Myeloid Leukemia (AML), induces broad transcriptional changes in AML cells before cell death induction. The regulated genes are particularly enriched in genes controlling cell proliferation and death, as well as inflammation and immunity. These transcriptional changes are preceded by DNR-dependent deSUMOylation of chromatin proteins, which limits both the positive and negative effects of DNR on transcription. Quantitative proteomics shows that proteins that are deSUMOylated in response to DNR are mostly transcription factors, transcriptional co-regulators and chromatin organizers. Among them, the CCCTC-binding factor CTCF is highly enriched at SUMO-binding sites found in cis-regulatory regions. This is notably the case at the promoter of the DNR-induced NFKB2 gene. Its induction is preceded by a SUMO-dependent reconfiguration of chromatin loops engaging its CTCF- and SUMO-bound promoter with distal cis-regulatory regions. Altogether, our work suggests that one of the earliest effects of DNR in AML cells is a SUMO-dependent transcriptional reprogramming.

molecular biology↗

bioRxiv2021

Contribution of 3D genome topological domains to genetic risk of cancers

Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in 3-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically-associating domains (TADs) and their borders. For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e. the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases display such a preferential location of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that TAD border enrichment in risk loci differ between cancers and non-cancer diseases. Different TAD border enrichments are observed in embryonic stem cells and differentiated cells, which agrees with an evolution along embryogenesis of the 3D genome organization into topological domains. Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically-insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with a direct effect on an individual gene, the other acting in interplay with 3D genome organization. Author summaryGenome-wide association studies comparing patients and healthy subjects have evidenced correlations between diseases and the presence of pointwise genetic variations known as single-nucleotide polymorphisms (SNPs). We exploit and extend this statistical analysis by investigating the location of risk loci, i.e. disease-associated SNPs, with respect to the 3D organization of the genome into spatially-insulated domains, the topologically-associating domains (TADs). We show that for certain diseases, mostly cancers, their associated risk loci are preferentially located in the borders of these topological domains. The predominance of cancers among these diseases is confirmed and even enhanced when considering only intergenic SNPs. A different enrichment behavior is observed in embryonic stem cells and derived cell lines at an early developmental stage, presumably due to the not fully mature TAD structure in these cells. Overall, our results show that genome variations in specific TAD borders may increase the risk of developing certain diseases, especially cancers. Our work underlines the importance of considering the genetic risk loci within their 3D genomic context, and suggests a role of 3D genome partitioning into topological domains in the genetic risk which differs between cancers and non-cancer diseases.

genetics↗