Lymphoid-Specific Helicase (HELLS) Is Essential for Meiotic Progression in Mouse Spermatocytes1

Abstract

Lymphoid-specific helicase (HELLS; also known as LSH) is a member of the SNF2 family of chromatin remodeling proteins. Because Hells-null mice die at birth, a phenotype in male meiosis cannot be studied in these animals. Allografting of testis tissue from Hells(-/-) to wild-type mice was employed to study postnatal germ cell differentiation. Testes harvested at Day 18.5 of gestation from Hells(-/-), Hells(+/-), and Hells(+/+) mice were grafted ectopically to immunodeficient mice. Bromodeoxyuridine incorporation at 1 wk postgrafting revealed fewer dividing germ cells in grafts from Hells(-/-) than from Hells(+/+) mice. Whereas spermatogenesis proceeded through meiosis with round spermatids in grafts from Hells heterozygote and wild-type donor testes, spermatogenesis arrested at stage IV, and midpachytene spermatocytes were the most advanced germ cell type in grafts from Hells(-/-) mice at 4, 6, and 8 wk after grafting. Analysis of meiotic configurations at 22 days posttransplantation revealed an increase in Hells(-/-) spermatocytes with abnormal chromosome synapsis. These results indicate that in the absence of HELLS, proliferation of spermatogonia is reduced and germ cell differentiation arrested at the midpachytene stage, implicating an essential role for HELLS during male meiosis. This study highlights the utility of testis tissue grafting to study spermatogenesis in animal models that cannot reach sexual maturity.

Developmental windows of susceptibility for epigenetic inheritance through the male germline

“…Inference that meiotic progression defects in DNMT3L-deficient spermatocytes are due to altered DNA methylation is furthermore supported by findings in other mouse mutants affecting epigenetic modulators, such as the SNF-2like helicase LSH, and the piRNA-binding protein MIWI2 (66)(67)(68). These mutants (79)(80)(81).…”

Genome-wide DNA methylation patterns in LSH mutant reveals de-repression of repeat elements and redundant epigenetic silencing pathways

“…Hells À/À mice die perinatally and exhibit multiple tissue deficiencies including stem cell defects. This indicates that HELLS is critical for normal development (Geiman and Muegge 2000;Geiman et al 2001;Sun et al 2004;De La Fuente et al 2006;Zeng et al 2011). Multiple pathways regulate DNA methylation, but it remains largely unknown how specific factors control methylation at a given site.…”

SNF2 family ATPase LSH promotes phosphorylation of H2AX and efficient repair of DNA double-strand breaks in mammalian cells

“…Knockout of Lsh (Hells) gene in mice leads to postnatal lethality and 50-70% reduction in the global levels of DNA methylation, including repetitive sequences and large chromosomal domains throughout the genome (Dennis et al, 2001;Myant et al, 2011;Tao et al, 2011). In addition, Lsh 2/2 embryos exhibit defects in male and female meiosis, which are manifested by incomplete chromosome synapses and failure to load crossover-associated foci (De La Fuente et al, 2006;Zeng et al, 2011). It has been hypothesised that LSH remodels chromatin to render DNA accessible to DNA methyltransferase enzymes and therefore it supports de novo DNA methylation and stable gene silencing (Zhu et al, 2006).…”