Biology subjects

Lefrancois-Martinez, A.-M.

Publications and source records attributed to Lefrancois-Martinez, A.-M..

4 recordsLinked to original sources

bioRxiv2026

PKA disrupts adult ovarian identity circuits through direct inhibition of TRIM28-chromatin binding

Functional ovarian plasticity depends on the granulosa cell (GC) fate determination, differentiation, oocyte support and steroid production. After birth, GC identity must be maintained in differentiating follicles, while from puberty, ovarian plasticity is cyclically challenged by gonadotropic hormones. TRIM28-FOXL2 interactions form a key chromatin component maintaining ovarian identity programs and repressing testis-specific genes. This TRIM28 role depends on its E3-SUMO-ligase activity, suggesting SUMOylation in GC can be regulated by transient hormonal cues, although hormonal involvement in modulating GC identity remains to be established. Here, we demonstrated the in vivo interplay between gonadotropic-PKA-signaling and hypo-SUMOylation waves underlying ovarian GC plasticity. In vitro TRIM28 mutagenesis and phospho-proteomics demonstrated direct PKA inhibitory control on TRIM28. This prompted us to highlight SUMOylation alterations in Carney Complex ovarian lesions resulting from chronic PKA activity from rare genetic mutations. Using mutant models, transcriptomics and TRIM28/FOXL2-ChIP-Seq analyses, we specified the in vivo PKA inhibitory mechanisms on TRIM28/FOXL2 chromatin binding and its consequences on adult ovarian somatic cell identity. Together, our data support an integrative model where gonadotrophin pulses create transient windows of PKA-mediated TRIM28 phosphorylation, hypo-SUMOylation, and FOXL2-TRIM28 destabilization. This positions SUMOylation dynamics as central integrator of hormonal signaling and epigenetic identity maintenance in the ovary.

physiology↗

bioRxiv2026

TRIM28 preserves ovarian identity by stabilising lineage-specific transcription factor hubs

Maintenance of ovarian cell identity is required throughout life to prevent the activation of the testicular program, but the epigenetic mechanisms underlying this process remain poorly understood. Although TRIM28 is required to prevent granulosa-to-Sertoli transdifferentiation, it can act both as a regulator of H3K9me3-dependent heterochromatin and as a transcriptional activator through its E3 SUMOligase activity. Here, we combined CUT&RUN, ATAC-seq and RNA-seq to define the respective contributions of these activities to maintain ovarian cell identity. Strikingly, only a small fraction of TRIM28-bound regions was associated with H3K9me3. Although Trim28 deletion induced focal H3K9me3 loss, it had limited transcriptional consequences and primarily affected repetitive elements rather than regions controlling testis-determining genes. In contrast, Trim28 loss led to reductions in chromatin accessibility and H3K27ac at regions enriched for ovarian transcription factor (TF) motifs FOXL2, NR5A2, ESR2 and RUNX1. Moreover, TRIM28 was frequently co-localized with these TFs on chromatin, and the accessibility and the SUMOylation at these co-bound regions were reduced by Trim28 deletion. Together, our findings identify TRIM28 as a central organizer of ovarian TF hubs whose predominant function is to preserve granulosa cell identity through stabilization of lineage-specific TFs rather than H3K9me3-dependent heterochromatin. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/739817v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@b39856org.highwire.dtl.DTLVardef@d65435org.highwire.dtl.DTLVardef@132974borg.highwire.dtl.DTLVardef@6ad72f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2022

Sexually dimorphic activation of innate antitumour immunity prevents adrenocortical carcinoma development

In contrast with most cancers, adrenocortical carcinomas (ACC) are more frequent in women than men, but the underlying mechanisms of this sexual dimorphism remain elusive. Homozygous deletion of the negative WNT pathway regulator ZNRF3 is the most frequent alteration in ACC patients. Here, we show that Cre-mediated inactivation of Znrf3 in steroidogenic cells of the mouse adrenal cortex is associated with sexually dimorphic tumour progression. Indeed, although most knockout female mice develop metastatic carcinomas over an 18 month-time course, adrenal hyperplasia gradually regresses in male knockout mice. This male-specific regression is associated with induction of senescence and recruitment of macrophages, which differentiate as active phagocytes that clear-out senescent preneoplastic cells. Macrophage recruitment is also observed in female mice. However, it is delayed and dampened compared to males, which allows for tumour progression. Interestingly, testosterone treatment of female knockouts is sufficient to induce senescence, recruitment of phagocytic macrophages and regression of hyperplasia. We further show that although macrophages are present within adrenal tumours at 18 months, MERTKhigh active phagocytes are mostly found in indolent lesions in males but not in aggressive tumours in females. Consistent with our observations in mice, analysis of RNA sequencing data from the TCGA cohort of ACC shows that phagocytic macrophages are more prominent in men than women and associated with better prognosis. Altogether, these data establish that phagocytic macrophages prevent aggressive ACC development in male mice and suggest that they may play a key role in the unusual sexual dimorphism of ACC in patients.

cancer biology↗

bioRxiv2021

Displacement of PKA catalytic subunit from AKAP signaling islands drives pathology in Cushing's syndrome

Mutations in the catalytic subunit of protein kinase A (PKAc) drive the stress hormone disorder adrenal Cushings syndrome. Here we define mechanisms of action for the PKAc-L205R and W196R variants. Both Cushings mutants are excluded from A kinase anchoring protein (AKAP) signaling islands and consequently diffuse throughout the cell. Kinase-dead experiments show that PKA activity is required for cortisol hypersecretion. However, kinase activation is not sufficient, as only cAMP analog drugs that displace native PKAc from AKAPs enhance cortisol release. Rescue experiments that incorporate mutant PKAc into AKAP signaling islands abolish cortisol overproduction, indicating that kinase anchoring restores normal endocrine function. Phosphoproteomics show that PKAc-L205R and W196R engage different mitogenic signaling pathways. ERK activity is elevated in adrenal-specific PKAc-W196R knock-in mice. Conversely, PKAc-L205R attenuates Hippo signaling, thereby upregulating the YAP/TAZ transcriptional co-activators. Thus, aberrant localization of each Cushings variant promotes the transmission of a distinct downstream pathogenic signal.

molecular biology↗