한빛사논문
- 조회189
Suk- Hyun Honga, Glenda Castroa, Dan Wanga,1, Russell Nofsingera, Maureen Kaneb, Alexandra Foliasb, Annette R. Atkinsa, Ruth T. Yua, Joseph L. Napolib, Paolo Sassone- Corsic, Dirk G. de Rooijd, Christopher Liddlee, Michael Downesa, and Ronald M. Evansa,2
aGene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
bDepartment of Nutritional Sciences and Toxicology, The University of California, Berkeley, CA 94720;
cDepartment of Biological Chemistry, Center for Epigenetics and Metabolism, U1233 INSERM, University of California, Irvine, CA 92697;
dReproductive Biology Group, Division of Developmental Biology, Department of Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, The Netherlands; and
eStorr Liver Centre, The Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead, NSW 2145, Australia
1Present address: Oncogenesis Thematic Research Center—Translational Research, Bristol Myers Squibb, San Diego, CA 92121.
2To whom correspondence may be addressed. : Ronald M. Evans
Abstract
Despite numerous female contraceptive options, nearly half of all pregnancies are unintended. Family planning choices for men are currently limited to unreliable condoms and invasive vasectomies with questionable reversibility. Here, we report the development of an oral contraceptive approach based on transcriptional disruption of cyclical gene expression patterns during spermatogenesis. Spermatogenesis involves a continuous series of self-renewal and differentiation programs of spermatogonial stem cells (SSCs) that is regulated by retinoic acid (RA)–dependent activation of receptors (RARs), which control target gene expression through association with corepressor proteins. We have found that the interaction between RAR and the corepressor silencing mediator of retinoid and thyroid hormone receptors (SMRT) is essential for spermatogenesis. In a genetically engineered mouse model that negates SMRT-RAR binding (SMRTmRID mice), the synchronized, cyclic expression of RAR-dependent genes along the seminiferous tubules is disrupted. Notably, the presence of an RA-resistant SSC population that survives RAR de-repression suggests that the infertility attributed to the loss of SMRT-mediated repression is reversible. Supporting this notion, we show that inhibiting the action of the SMRT complex with chronic, low-dose oral administration of a histone deacetylase inhibitor reversibly blocks spermatogenesis and fertility without affecting libido. This demonstration validates pharmacologic targeting of the SMRT repressor complex for non-hormonal male contraception.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-03-13)
- 국외 연구진
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