Sepponen, K., Lundin, K., Yohannes, D. A., Vuoristo, S., Balboa, D., Poutanen, M., Ohlsson, C., Hustad, S., Bifulco, E., Paloviita, P., Otonkoski, T., Ritvos, O., Sainio, K., Tapanainen, J. S., & Tuuri, T. (2022). Steroidogenic factor 1 (NR5A1) induces multiple transcriptional changes during differentiation of human gonadal-like cells. In Differentiation (Vol. 128, pp. 83–100). Elsevier BV. https://doi.org/10.1016/j.diff.2022.08.001
Steroidogenic factor 1 (NR5A1) induces multiple transcriptional changes during differentiation of human gonadal-like cells
|Author:||Sepponen, Kirsi1; Lundin, Karolina1; Yohannes, Dawit A.1,2;|
1Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
2Research Programs Unit, Translational Immunology & Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
3Department of Obstetrics and Gynecology, Functional Embryo Genomics Lab, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
4Stem Cells and Metabolism Research Program and Children's Hospital, Faculty of Medicine, University of Helsinki, Helsinki, Finland
5Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland
6Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7Core Facility for Metabolomics, University of Bergen, Bergen, Norway
8Department of Clinical Science, University of Bergen, Bergen, Norway
9Department of Biological Sciences, University of Bergen, Bergen, Norway
10Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
11Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
12Department of Obstetrics and Gynecology, University Hospital of Oulu, University of Oulu, Medical Research Center Oulu and PEDEGO Research Unit, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 12 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2023061956833
|Publish Date:|| 2023-06-19
Nuclear receptor subfamily 5 group A member 1 (NR5A1) encodes steroidogenic factor 1 (SF1), a key regulatory factor that determines gonadal development and coordinates endocrine functions. Here, we have established a stem cell-based model of human gonadal development and applied it to evaluate the effects of NR5A1 during the transition from bipotential gonad to testicular cells. We combined directed differentiation of human induced pluripotent stem cells (46,XY) with activation of endogenous NR5A1 expression by conditionally-inducible CRISPR activation. The resulting male gonadal-like cells expressed several Sertoli cell transcripts, secreted anti-Müllerian hormone and responded to follicle-stimulating hormone by producing sex steroid intermediates. These characteristics were not induced without NR5A1 activation. A total of 2691 differentially expressed genetic elements, including both coding and non-coding RNAs, were detected immediately following activation of NR5A1 expression. Of those, we identified novel gonad-related putative NR5A1 targets, such as SCARA5, which we validated also by immunocytochemistry. In addition, NR5A1 activation was associated with dynamic expression of multiple gonad- and infertility-related differentially expressed genes. In conclusion, by combining targeted differentiation and endogenous activation of NR5A1 we have for the first time, been able to examine in detail the effects of NR5A1 in early human gonadal cells. The model and results obtained provide a useful resource for future investigations exploring the causative reasons for gonadal dysgenesis and infertility in humans.
|Pages:||83 - 100|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
3123 Gynaecology and paediatrics
This work was supported by the Sigrid Jusélius Foundation, the Academy of Finland (Grant 295760), Helsinki University Hospital Funds, and the Novo Nordisk Foundation (Grant 10825).
RNA sequencing raw and processed read files have been deposited in NCBI's Gene Expression Omnibus and can be accessed through GEO Series accession number GSE186606. All material unique to this study is available from the corresponding author upon request.
© 2022 The Authors. Published by Elsevier B.V. on behalf of International Society of Differentiation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).