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CHD2 maintains spermatogonial self-renewal by promoting chromatin activity and mRNA stability

ABSTRACT: Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE198581 | GEO | 2022/11/15

REPOSITORIES: GEO

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CHD2 maintains spermatogonial self-renewal by promoting chromatin activity and mRNA stability

Project description:Chromodomain Helicase DNA-binding Domain 2 (CHD2), as a chromatin remodeling factor, was shown to be involved in the regulation of gene expression in embryonic development, neurodevelopment and myelopoiesis. However, its role in male germ cell development has not been elucidated. Here, we confirmed that CHD2 is abundantly expressed throughout the male germ cells with the highest expression in the spermatocytes of meiosis I. By constructing a heterozygous gene knockout mouse model of Chd2 (Chd2+/-), we demonstrated that CHD2 haploinsufficiency resulted in testicular developmental delay and increased rate of abnormal sperm in mice. DNA damage repair, synapsis and cell proliferation during spermatogenesis are impaired in Chd2+/- mice. In vitro experiments in C18-4 and GC-1 spg cells showed that CHD2 knockdown inhibits spermatogonial self-renewal. Mechanically, CHD2 maintained the enrichment of H3K4me3 in Ccnb1 and Ccnd2 promoter consequently promoting the transcription of Ccnb1 and Ccnd2. In addition, by interacting with cleavage stimulation factor CSTF3, CHD2 binds Oct4, Plzf mRNA and upregulates the expression of OCT4 and PLZF by improving mRNA stability. This is the first time to reveal the role and mechanism of CHD2 in maintaining spermatogonial self-renewal by promoting chromatin activity and mRNA stability in spermatogenesis.

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Glis3 plays a crucial role in spermatogenesis [848_827]

Project description:We show that Glis3 is expressed in gonocytes, SSCs and SPCs, but not in differentiated spermatogonia or subsequent stages of spermatogenesis nor in Sertoli or Leydig cells. We further demonstrate that Glis3-deficiency causes a severe impairment in spermatogenesis in mice. Although the number of gonocytes was slightly diminished in Glis3KO testis, the number undifferentiated, PLZF+ spermatogonia was dramatically reduced leading to a virtual block in the progression of spermatogenesis. Gene expression profiling showed that the expression of a number of genes associated with self-renewal and differentiation of spermatogonial cells was significantly decreased in 1-week-old Glis3KO2 testis. These included a set of GDNF-dependent genes, such as Etv5, Bcl6b, Lhx1, Brachyury, Id4, and Pou3f1, and GDNF-independent genes, such as FoxO1, Oct4, and Zbtb16. Impairment of the nuclear localization of FoxO1 may be in part responsible for the reduced expression of Ret, Lhx1, and Sall4 in Glis3KO2 testis. Our study identifies Glis3 as a novel and critical regulator of early stages of spermatogenesis. Testis total RNAs were purified from 4 WT and 4 Glis3KO2 at 1 week old age, and 3WT and 3 Glis3KO2 at 3 week-old age. Then the samples were applied to Agilent mouse genome chip.

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Glis3 plays a crucial role in spermatogenesis [923]

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The Human Testis Cell Atlas via Single-cell RNA-seq (Healthy men scRNA-seq data set)

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