Dataset Information

ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice

ABSTRACT: During spermiogenesis, nuclear remodeling occurs where histones are initially replaced by transition proteins (TNPs) and subsequently by protamines, a process essential for sperm maturation. Although the degradation of histones and TNPs is thought to be essential for sperm nuclear remodeling, the underlying mechanisms, particularly those governing TNP degradation, remain poorly understood. In this study, we investigated the role of the ankyrin repeat-containing SOCS box protein 9 (ASB9) during spermiogenesis and found that its deficiency causes TNP2 retention, leading to a failure of the histone-to-protamine transition in both humans and mice. This disruption consequently causes male infertility, characterized by sperm head malformation and impairments in fertilization and early embryonic development. Mechanistically, we found that ASB9 assembles a testis-specific Cullin-RING ligase (CRL) complex—TNP2–ASB9–ELOB/C–CUL5–RBX1—that mediates the ubiquitin-dependent degradation of TNP2 to facilitate the histone-to-protamine transition during spermiogenesis. Thus, our study is the first to uncover the mechanism underlying TNP2 degradation and highlights the critical role of ASB9 in male fertility through the CRL complex-mediated ubiquitination pathway, thereby expanding the fundamental understanding of nuclear remodeling during spermiogenesis.

ORGANISM(S): Mus Musculus

SUBMITTER: Ying Shen

PROVIDER: PXD070974 | iProX | Wed Nov 19 00:00:00 GMT 2025

REPOSITORIES: iProX

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ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice.

Zhao Shikun S Shen Gan G Ruan Tiechao T Zhuo Liangchai L Wang Yan Y Wang Xiang X Tian Yunchuan Y Tang Xinyao X Ma Jun J Jiang Xiaohui X Zhang Yingteng Y Jiang Chuan C Xie Anan A Shang Xuejun X Wang Jing J Yang Yihong Y Shen Ying Y

Proceedings of the National Academy of Sciences of the United States of America 20260331 14

During spermiogenesis, nuclear remodeling occurs where histones are sequentially replaced by transition proteins (TNPs) and protamines, a process essential for sperm maturation. Although the degradation of histones and TNPs is thought to be essential for sperm nuclear remodeling, the underlying mechanisms, particularly those governing TNP degradation, remain poorly understood. In this study, we investigated the role of the ankyrin repeat-containing SOCS box protein 9 (ASB9) during spermiogenesis ...[more]

PMID: 41915740

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Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Mnase sensitivity of sperm DNA, indicating nucleosomal, not protamine, packaging was altered in mice by manipulating poly(ADP-ribose) metabolism in adult males using a specific PARP inhibitor for 6 weeks. Abnormal sperm nucleosomal organization of males analyzed by these tiling arrays was compared with differential gene expression in 2 cell embryos fathered by these males analyzed by separate gene expression arrays and RNA sequencing.

Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Mnase sensitivity of sperm DNA, indicating nucleosomal, not protamine, packaging was altered in mice by manipulating poly(ADP-ribose) metabolism in adult males using Parg gene disruption (Parg(110)-/-). Abnormal sperm nucleosomal organization of males analyzed by these tiling arrays was compared with differential gene expression in individual 2 cell embryos fathered by these males analyzed in separate expression microarrays.

Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. 9 WT samples in 3 groups of 3. Each group consists of 3 eggs fertilized by the same father. 9 KO samples in the same setup. Samples are single 2-cell embryos. All mice are in a 129SVE (=129S6/SvEvTac, Taconic) background.

Project description:To achieve the extreme nuclear condensation necessary for sperm function, most histones are replaced with protamines during spermiogenesis in mammals. Mature sperm retain only a small fraction of nucleosomes, which are, in part, enriched on gene regulatory sequences, and recent findings suggest that these retained histones provide epigenetic information that regulates expression of a subset of genes involved in embryo development after fertilization. We addressed this tantalizing hypothesis by analyzing two mouse models exhibiting abnormal histone positioning in mature sperm due to impaired poly(ADP-ribose) (PAR) metabolism during spermiogenesis and identified altered sperm histone retention in specific gene loci genome-wide using MNase digestion-based enrichment of mononucleosomal DNA. We then set out to determine the extent to which expression of these genes was altered in embryos generated with these sperm. For control sperm, most genes showed some degree of histone association, unexpectedly suggesting that histone retention in sperm genes is not an all-or-none phenomenon and that a small number of histones may remain associated with genes throughout the genome. The amount of retained histones, however, was altered in many loci when PAR metabolism was impaired. To ascertain whether sperm histone association and embryonic gene expression are linked, the transcriptome of individual 2-cell embryos derived from such sperm was determined using microarrays and RNA sequencing. Strikingly, a moderate but statistically significant portion of the genes that were differentially expressed in these embryos also showed different histone retention in the corresponding gene loci in sperm of their fathers. These findings provide new evidence for the existence of a linkage between sperm histone retention and gene expression in the embryo. Seven WT (wild-type) samples of one 2-cell embryo each, all from fathers treated with saline (controls). Each group A, B, D consists of eggs fertilized by the same father (each sample is a single 2 cell embryo, 2CE). Ten samples of 2CE from fathers treated with PJ34 (PARP inhibitor) for 6 weeks, in the same setup (PJ-MTM11-1 to PJ34-MTM14-2, offspring from fathers MTM11, MTM13 or MTM14). All mice are wild-type, strain 129SVE (=129S6/SvEvTac, Taconic).

Dataset Information

ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice

Publications

ASB9 promotes ubiquitin-mediated degradation of TNP2 to facilitate histone-to-protamine transition in humans and mice.

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