@article{607c184d45fb4ba8a586f9cba859fcad,
title = "PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis",
abstract = "Spermatogenesis is a complex process of sperm generation, including mitosis, meiosis, and spermiogenesis. During spermiogenesis, histones in post-meiotic spermatids are removed from chromatin and replaced by protamines. Although histone-to-protamine exchange is important for sperm nuclear condensation, the underlying regulatory mechanism is still poorly understood. Here, we identify PHD finger protein 7 (PHF7) as an E3 ubiquitin ligase for histone H3K14 in post-meiotic spermatids. Generation of Phf7-deficient mice and Phf7 C160A knockin mice with impaired E3 ubiquitin ligase activity reveals defects in histone-to-protamine exchange caused by dysregulation of histone removal factor Bromodomain, testis-specific (BRDT) in early condensing spermatids. Surprisingly, E3 ubiquitin ligase activity of PHF7 on histone ubiquitination leads to stabilization of BRDT by attenuating ubiquitination of BRDT. Collectively, our findings identify PHF7 as a critical factor for sperm chromatin condensation and contribute to mechanistic understanding of fundamental phenomenon of histone-to-protamine exchange and potential for drug development for the male reproduction system. Histone-to-protamine exchange is essential for functional sperm. Kim et al. demonstrate that PHF7 is an E3 ubiquitin ligase for histone H3, and that PHF7-mediated histone ubiquitination regulates BRDT stability during histone removal. Mice with impaired Phf7 show dysfunctional sperm caused by defects in histone ubiquitination and histone-to-protamine exchange.",
keywords = "BRDT, H3K14ub, H4 hyperacetylation, PHF7, histone removal, histone-to-protamine exchange, spermiogenesis",
author = "Kim, {Chang Rok} and Taichi Noda and Hyunkyung Kim and Gibeom Kim and Seongwan Park and Yongwoo Na and Seiya Oura and Keisuke Shimada and Injin Bang and Ahn, {Jun Yeong} and Kim, {Yong Ryoul} and Oh, {Se Kyu} and Choi, {Hee Jung} and Kim, {Jong Seo} and Inkyung Jung and Ho Lee and Yuki Okada and Masahito Ikawa and Baek, {Sung Hee}",
note = "Funding Information: We thank members of the Epigenetic Code and Diseases Research Center for discussions and technical assistance. This work was supported by Creative Research Initiatives Program ( Research Center for Epigenetics Code and Diseases , grant NRF-2017R1A3B1023387 to S.H.B.); the Science Research Center program (grant NRF-2016R1A5A1010764 to S.H.B.); Korea University (grant K1925011 to H.K.); the Institute for Basic Science (grant IBS-R008-D1 to J.-S.K.); Korean Ministry of Health and Welfare , funded by the Korean Government (grant HI17C0328 to I.J.); and Ministry of Education, Culture, Sports, Science, and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants ( JP18K14612 to T.N., JP19J21619 to S.O., JP17K17852 to K.S., and 19H05750 to M.I.). Phf7-floxed mouse was kindly provided from the Korea Mouse Phenotyping Center. Funding Information: We thank members of the Epigenetic Code and Diseases Research Center for discussions and technical assistance. This work was supported by Creative Research Initiatives Program (Research Center for Epigenetics Code and Diseases, grant NRF-2017R1A3B1023387 to S.H.B.); the Science Research Center program (grant NRF-2016R1A5A1010764 to S.H.B.); Korea University (grant K1925011 to H.K.); the Institute for Basic Science (grant IBS-R008-D1 to J.-S.K.); Korean Ministry of Health and Welfare, funded by the Korean Government (grant HI17C0328 to I.J.); and Ministry of Education, Culture, Sports, Science, and Technology (MEXT)/Japan Society for the Promotion of Science (JSPS) KAKENHI grants (JP18K14612 to T.N. JP19J21619 to S.O. JP17K17852 to K.S. and 19H05750 to M.I.). Phf7-floxed mouse was kindly provided from the Korea Mouse Phenotyping Center. C.R.K. T.N. Y.O. M.I. and S.H.B. designed the experiments; C.R.K. T.N. G.K. H.L. and M.I. generated and maintained Phf7f/f, Phf7tKO, Phf7C160A, and Phf7FLAG mice; C.R.K. T.N. S.O. and K.S. analyzed mouse phenotype; C.R.K. T.N. J.-Y.A. and S.K.O. performed histological assays; C.R.K. H.K. G.K. and Y.R.K. performed the cell biology and biochemistry experiments; C.R.K. S.P. and I.J. performed single-cell RNA sequencing analysis; Y.N. I.B. and J.-S.K. performed LC-MS/MS analysis; I.B. and H.-J.C. produced recombinant E1 and PHF7 protein; C.R.K. T.N. I.J. M.I. and S.H.B. wrote the manuscript; all authors contributed to data analysis. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jul,
day = "28",
doi = "10.1016/j.celrep.2020.107950",
language = "English",
volume = "32",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}