Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility

Cannarella, Rossella; Condorelli, Rosita A.; Mongioì, Laura M.; Vignera, Sandro La; Calogero, Aldo E.

doi:10.3390/ijms21051728

Cited by 84 publications

(62 citation statements)

References 46 publications

(69 reference statements)

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“…In addition, we also observed Srsf3 and Ruvbl1 in our proteome analysis which have been implicated recently as sperm-carried molecular factors involved in oocyte fertilization and embryo growth (Fig. 6E) (106).…”

Section: Discussionsupporting

confidence: 74%

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

Vasantha

Bhaduri

Ravikkumar

et al. 2020

Preprint

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Abstract Background: H1T2/H1FNT is a germ cell specific linker histone variant expressed during spermiogenesis specifically in round and elongating spermatids. Infertile phenotype of homozygous H1T2 mutant male mice revealed the essential function of H1T2 for the DNA condensation and histone to protamine replacement in spermiogenesis. However, the mechanism by which H1T2 imparts the inherent polarity within spermatid nucleus including the additional protein partners and the genomic domains occupied by this linker histone are unknown.Results: Sequence analysis revealed the presence of Walker motif, SR domains and putative coiled-coil domains in the C-terminal domain of rat H1T2 protein. Genome wide occupancy analysis using highly specific antibody against the CTD of H1T2 demonstrated the binding of H1T2 to the LINE L1 repeat elements and to a significant percentage of the genic regions (promoter-TSS, exons and introns) of the rat spermatid genome. Immunoprecipitation followed by mass spectrometry analysis revealed the open chromatin architecture of H1T2 occupied chromatin encompassing the H4 acetylation and other histone PTMs characteristic of transcriptionally active chromatin. In addition, the present study has identified the interacting protein partners of H1T2 associated chromatin mainly as nucleo-skeleton components, RNA binding proteins and chaperones.Conclusions: Linker histone H1T2 possesses unique domain architecture which can account for the specific functions associated with chromatin remodeling events facilitating the initiation of histone to transition proteins/protamine transition in the polar apical spermatid genome. Our results directly establish the unique function of H1T2 in nuclear shaping associated with spermiogenesis by mediating the interaction between chromatin and nucleo-skeleton, positioning the epigenetically specialized chromatin domains involved in transcription coupled histone replacement initiation towards the apical pole of round/elongating spermatids.

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Section: Discussionsupporting

confidence: 74%

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

Vasantha

Bhaduri

Ravikkumar

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…IP/WB analysis also validated several of proteins involved in splicing, mRNA export, and transcript stability like Ddx5, Ybx2, Elavl1, Pabp1 and Ilf3, known to be associated with transcriptionally active chromatin domain. In addition, we also observed Srsf3 and Ruvbl1 in our proteome analysis which have been implicated recently as sperm-carried molecular factors involved in oocyte fertilization and embryo growth (Fig 6E) (113).…”

Section: Discussionsupporting

confidence: 74%

Genome-wide occupancy reveals the localization of H1T2 (H1fnt) to repeat regions and a subset of transcriptionally active chromatin domains in rat spermatids

Vasantha

Bhaduri

Ravikkumar

et al. 2020

Preprint

View full text Add to dashboard Cite

Background H1T2/H1FNT is a germ cell specific linker histone variant expressed during spermiogenesis specifically in round and elongating spermatids. Infertile phenotype of homozygous H1T2 mutant male mice revealed the essential function of H1T2 for the DNA condensation and histone to protamine replacement in spermiogenesis. However, the mechanism by which H1T2 imparts the inherent polarity within spermatid nucleus including the additional protein partners and the genomic domains occupied by this linker histone are unknown.Results Sequence analysis revealed the presence of Walker motif, SR domains and putative coiled-coil domains in the C-terminal domain of rat H1T2 protein. Genome wide occupancy analysis using highly specific antibody against the CTD of H1T2 demonstrated the binding of H1T2 to the LINE L1 repeat elements and to a significant percentage of the genic regions (promoter-TSS, exons and introns) of the rat spermatid genome. Immunoprecipitation followed by mass spectrometry analysis revealed the open chromatin architecture of H1T2 occupied chromatin encompassing the H4 acetylation and other histone PTMs characteristic of transcriptionally active chromatin. In addition, the present study has identified the interacting protein partners of H1T2 associated chromatin mainly as nucleo-skeleton components, RNA binding proteins and chaperones.Conclusions Linker histone H1T2 possesses unique domain architecture which can account for the specific functions associated with chromatin remodeling events facilitating the initiation of histone to transition proteins/protamine transition in the polar apical spermatid genome. Our results directly establish the unique function of H1T2 in nuclear shaping associated with spermiogenesis by mediating the interaction between chromatin and nucleo-skeleton, positioning the epigenetically specialized chromatin domains involved in transcription coupled histone replacement initiation towards the apical pole of round/elongating spermatids.

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“…To evaluate the expression of human infertility genes in our cell clusters, we retrieved 105 genes from Cannarella et al 61 and the Online Inheritance in Man (OMIM) database using search terms of "male infertility" and "spermatogenic failure." Genes associated with pituitary, hypothalamus and gonadal somatic cells were excluded.…”

Section: Quantification and Statistical Analysismentioning

confidence: 99%

Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

et al. 2020

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Establishment of spermatogonia throughout the fetal and postnatal period is essential for production of spermatozoa and male fertility. Here, we establish a protocol for in vitro reconstitution of human prospermatogonial specification whereby human primordial germ cell (PGC)-like cells differentiated from human induced pluripotent stem cells are further induced into M-prospermatogonia-like cells and T1 prospermatogonia-like cells (T1LCs) using long-term cultured xenogeneic reconstituted testes. Single cell RNA-sequencing is used to delineate the lineage trajectory leading to T1LCs, which closely resemble human T1-prospermatogonia in vivo and exhibit gene expression related to spermatogenesis and diminished proliferation, a hallmark of quiescent T1 prospermatogonia. Notably, this system enables us to visualize the dynamic and stage-specific regulation of transposable elements during human prospermatogonial specification. Together, our findings pave the way for understanding and reconstructing human male germline development in vitro.

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Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility

Cited by 84 publications

References 46 publications

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

Genome-Wide Occupancy Reveals The Localization of H1T2 (H1fnt) To Repeat Regions and A Subset of Transcriptionally Active Chromatin Domains in Mammalian Spermatids

Genome-wide occupancy reveals the localization of H1T2 (H1fnt) to repeat regions and a subset of transcriptionally active chromatin domains in rat spermatids

Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

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