Biology subjects

Rafiee, M.-R.

Publications and source records attributed to Rafiee, M.-R..

3 recordsLinked to original sources

bioRxiv2023

FOXL2 interaction with different binding partners regulates the dynamics of granulosa cell differentiation across ovarian development

The transcription factor FOXL2 is required in ovarian somatic cells for female fertility. Differential timing of Foxl2 deletion, in embryonic versus adult mouse ovary, leads to distinctive outcomes suggesting different roles across development. Here, we comprehensively investigated FOXL2s role through a multi-omics approach to characterise gene expression dynamics and chromatin accessibility changes, coupled with genome-wide identification of FOXL2 targets and on-chromatin interacting partners in granulosa cells across ovarian development. We found that FOXL2 regulates more targets postnatally, through interaction with factors regulating primordial follicle activation (PFA) and steroidogenesis. Deletion of one interactor, Ubiquitin specific protease 7 (USP7), induces PFA blockage, impaired ovary development and sterility. Our datasets constitute a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.

developmental biology↗

bioRxiv2023

Human Integrator provides a quality checkpoint during elongation to facilitate RNA polymerase II processivity

Integrator is a multi-subunit complex that directly interacts with the C-terminal domain (CTD) of RNA polymerase II (RNAPII). Through its RNA endonuclease activity, Integrator is required for 3'-end processing of both non-coding and coding transcripts. Here we demonstrate that depleting Integrator subunit 11 (INTS11), the main catalytic subunit of the Integrator complex, leads to a global elongation defect as a result of decreased polymerase processivity. We observe this defect in the region approximately 12 to 35 kb downstream of the transcription start site (TSS), where RNAPII normally transitions to its maximum processivity. We also identify an important role for INTS11, possibly in association with RNAPII CTD phospho-Tyr1, in repressing antisense transcription upstream of active promoters, as well as repressing transcription of genic regions near AsiSI-induced double-strand breaks. Altogether, this study points toward a novel function of Integrator in promoting termination of incompetent RNAPII molecules while facilitating the transition to fully processive polymerase in order to enable efficient elongation.

molecular biology↗

bioRxiv2021

TRIM28-dependent SUMOylation protects the adult ovary from the male pathway

Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. In the mouse ovary, oestrogen receptors and FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying their protective effect is unknown. Here, we show that TRIM28 is required to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of Trim28, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type, different from gonadal embryonic progenitors. TRIM28 is recruited on chromatin in the proximity of FOXL2 to maintain the ovarian pathway and to repress testicular-specific genes. The role of TRIM28 in ovarian maintenance depends on its E3-SUMO ligase activity that regulates the sex-specific SUMOylation profile of ovarian-specific genes. Our study identifies TRIM28 as a key factor in protecting the adult ovary from the testicular pathway.

developmental biology↗