Abstract
The CCCTC-binding factor (CTCF) is an architectural protein that governs chromatin organization and gene expression in somatic cells. Here, we show that CTCF regulates chromatin compaction necessary for packaging of the paternal genome into mature sperm. Inactivation of Ctcf in male germ cells in mice (Ctcf-cKO mice) resulted in impaired spermiogenesis and infertility. Residual spermatozoa in Ctcf-cKO mice displayed abnormal head morphology, aberrant chromatin compaction, impaired protamine 1 incorporation into chromatin and accelerated histone depletion. Thus, CTCF regulates chromatin organization during spermiogenesis, contributing to the functional organization of mature sperm.
Highlights
In the gonads of mammalian organisms, diploid germ cells give rise to haploid gametes, egg and sperm
In order to study the function of CTCF during spermatogenesis, Ctcf was conditionally targeted in male germ cells
We found that conditional targeting of the Ctcf gene was restricted to the testis in mice heterozygous for the floxed Ctcf allele (Stra8-iCre-Ctcf wt/f) (Supplementary Fig. S1)
Summary
In the gonads of mammalian organisms, diploid germ cells give rise to haploid gametes, egg and sperm. The male germ cell differentiation process, spermatogenesis, takes place in testis[1,2]. The round spermatids subsequently undergo a series of morphological changes, in a process known as spermiogenesis, giving rise to mature sperm ( called spermatozoa)[3,4]. Binding of CTCF to DNA has been shown to contribute to the formation of three-dimensional DNA loops, mediating long-range chromatin interactions between different regulatory sequences in somatic cells[15,17]. Elongating spermatids in the testis and mature spermatozoa in the cauda epididymis of Ctcf-cKO mice displayed major defects in sperm head formation and chromatin compaction. Genes, expressed in round spermatids in the testis of wild-type mice and contributing to sperm formation, were found to be down-regulated in Ctcf-cKO mice. Mature spermatozoa in Ctcf-cKO mice showed abrogated histone retention and PRM1 recruitment to chromatin. CTCF contributes in a critical way to the differentiation process that controls formation of mature sperm
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