Affinity-tagged SMAD1 and SMAD5 mouse lines reveal transcriptional reprogramming mechanisms during early pregnancy

Author:

Liao Zian1234,Tang Suni14,Nozawa Kaori14,Shimada Keisuke5ORCID,Ikawa Masahito5ORCID,Monsivais Diana14ORCID,Matzuk Martin M.1234ORCID

Affiliation:

1. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, 77030, USA

2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

3. Graduate Program of Genetics and Genomics, Baylor College of Medicine, Houston, TX, 77030, USA

4. Center for Drug Discovery, Baylor College of Medicine, Houston, TX, 77030, USA

5. Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

Abstract

Endometrial decidualization, a prerequisite for successful pregnancies, relies on transcriptional reprogramming driven by progesterone receptor (PR) and bone morphogenetic protein (BMP)-SMAD1/SMAD5 signaling pathways. Despite their critical roles in early pregnancy, how these pathways intersect in reprogramming the endometrium into a receptive state remains unclear. To define how SMAD1 and/or SMAD5 integrate BMP signaling in the uterus during early pregnancy, we generated two novel transgenic mouse lines with affinity tags inserted into the endogenous SMAD1 and SMAD5 loci (Smad1HA/HAand Smad5PA/PA). By profiling the genome-wide distribution of SMAD1, SMAD5, and PR in the mouse uterus, we demonstrated the unique and shared roles of SMAD1 and SMAD5 during the window of implantation. We also showed the presence of a conserved SMAD1, SMAD5, and PR genomic binding signature in the uterus during early pregnancy. To functionally characterize the translational aspects of our findings, we demonstrated that SMAD1/5 knockdown in human endometrial stromal cells suppressed expressions of canonical decidual markers (IGFBP1, PRL, FOXO1) and PR-responsive genes (RORB, KLF15). Here, our studies provide novel tools to study BMP signaling pathways and highlight the fundamental roles of SMAD1/5 in mediating both BMP signaling pathways and the transcriptional response to progesterone (P4) during early pregnancy.

Publisher

eLife Sciences Publications, Ltd

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