Endometrial Proliferative Phase-Centered View on the Transcriptome Dynamics Across the Menstrual Cycle

The endometrium, the inner mucosal lining of the uterus, undergoes complex molecular and cellular changes across the menstrual cycle in preparation for embryo implantation. Transcrip-tome-wide analyses have mainly been utilized to study the endometrial receptivity, the prerequisite for successful implantation, with most of the studies, so far, comparing the endometrial transcriptomes between (i) secretory versus proliferative endometrium or (ii) mid-secretory versus early-secretory endometrium. In the current study, we provide the complete transcriptome description of the endometrium across the entire menstrual cycle and, for the first time, comprehensively characterize the proliferative phase of the endometrium. Our temporal transcriptome analysis includes five time points: mid-proliferative, late-proliferative (peri-ovulatory phase), early-secretory, mid-secretory, and late-secretory phases. Thus, we exhaustively unveil the transitions between the consecutive proliferative and secretory phases, highlighting their unique gene expression profiles and possible distinct biological functions. Transcriptome analysis reveals many differentially expressed genes (DEGs) across the menstrual cycle, most of which are phase-specific. As an example of the coordinated gene activity, the expression profile of his-tone-encoding genes within the HIST cluster on chromosome 6 showed an increase in cluster activity during the late-proliferative and a decline during the mid-secretory phase. Moreover, numerous DEGs are shared among all phases. In conclusion, in the current study, we delineate the endometrial proliferative phase-centered view of transcriptome dynamics across the menstrual cycle. Data analysis highlights significant transcriptomic and functional changes occurring during the late-proliferative phase – an essential transition point from the proliferative to the secretory phase. Future studies should explore how the biology of the late-proliferative phase endometrium impacts the achievement of mid-secretory endometrial receptivity or contributes to molecular aberrations leading to embryo implantation failure.