PKA disrupts adult ovarian identity circuits through direct inhibition of TRIM28-chromatin binding
- 1Institute of Genetics, Reproduction & Development (iGReD), CNRS, Inserm, University of Clermont-Auvergne, France
Abstract
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.
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BibTeX
@misc{chaleil2026disrupts,
title = {{PKA disrupts adult ovarian identity circuits through direct inhibition of TRIM28-chromatin binding}},
author = {F. CHALEIL and L. Le Gallic and I. Sahut-Barnola and J. Mordier and S. Le Gras and S. Roumeau and C. Keime and C. DJARI and A. Vigier and L. Badoil and P. VAL and J. C. POINTUD and C. A. Stratakis and F. Cammas and A. Martinez and F. Poulat and A.-M. Lefrancois-Martinez},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755598},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755598v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - PKA disrupts adult ovarian identity circuits through direct inhibition of TRIM28-chromatin binding
AU - F. CHALEIL
AU - L. Le Gallic
AU - I. Sahut-Barnola
AU - J. Mordier
AU - S. Le Gras
AU - S. Roumeau
AU - C. Keime
AU - C. DJARI
AU - A. Vigier
AU - L. Badoil
AU - P. VAL
AU - J. C. POINTUD
AU - C. A. Stratakis
AU - F. Cammas
AU - A. Martinez
AU - F. Poulat
AU - A.-M. Lefrancois-Martinez
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755598
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755598v1
AB - 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.
ER -