JMJD1C Exhibits Multiple Functions in Epigenetic Regulation during Spermatogenesis

Area of Science:

• Reproductive Biology
• Molecular Genetics
• Epigenetics

Background:

• Jmjd1C is a Jmjd1 family gene encoding demethylases for histone H3K9 and non-histone proteins.
• Jmjd1C is essential for successful mouse spermatogenesis.

Purpose of the Study:

• To investigate the function of Jmjd1C in spermatogenesis using a novel Jmjd1C loss-of-function mouse model.
• To elucidate the molecular mechanisms underlying Jmjd1C's role in male germ cell development and maintenance.

Main Methods:

• Analysis of a transgenic mouse strain with a Jmjd1C loss-of-function allele (β-geo cassette insertion).
• Examination of testicular histology and cellular morphology in homozygous Jmjd1C mutant mice.
• Assessment of histone modifications (H4K16 acetylation) and key gene expression (Oct4, NANOG) in testes.
• Investigation of potential protein-protein interactions (Jmjd1C with MDC1, HSP90).

Main Results:

• Jmjd1C deficiency caused malformations in postmeiotic sperm development and impaired long-term maintenance of undifferentiated spermatogonia.
• Abnormal spermatid organization and incomplete elongation were observed from the first spermatogenic wave onwards.
• Histone H4K16 acetylation significantly decreased, potentially due to disrupted Jmjd1C interactions with partner proteins.
• Reduced Oct4 expression and fewer NANOG/OCT4-expressing spermatogonia were noted in mature Jmjd1C homozygous testes.

Conclusions:

• Jmjd1C plays crucial, multifaceted roles throughout spermatogenesis, impacting both germ cell differentiation and stem cell self-renewal.
• Jmjd1C's function in maintaining spermatogonial stem cells may involve up-regulating Oct4 expression.
• Interactions with partner proteins like MDC1 and HSP90 are critical for JMJD1C's function during spermatogenesis.