Jhdm2a异常？小心不孕

hy2007

Possible Candidate Gene in Infertility Syndromes Described

October 17, 2007 — A new study has found that Jhdm2a, a gene that removes methyl groups from histones, plays a major regulatory role in spermatogenesis. The gene's protein product, JHDM2A (a histone demethylase 2A), controls the expression of 2 other genes responsible for packaging and condensing nuclear material during late stages of spermatogenesis. Blocking Jhdm2a activity results in abnormally shaped and mostly immotile sperm.

Published online ahead of print on October 17 in Nature, the report notes that previous mouse models have knocked out genes potentially involved in human infertility syndromes such as azoospermia and globozoospermia. However, the equivalent human genes have usually proven to be intact in these syndromes, leaving the field wide open for new candidate genes in human male infertility.

\"The causes of these syndromes are currently unknown,\" said senior author Yi Zhang, PhD, an investigator at Howard Hughes Medical Institute and professor in the Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, in an email to Medscape. \"Given that Jhdm2a is a new gene important for spermatogenesis, it is natural to think that Jhdm2a is a new candidate potentially involved in these syndromes.\"

When Jhmd2a is disrupted in mice, the protein product, JHMD2a, can no longer catalyze histone demethylation. Male mice homozygous for this deficit have smaller testes, low sperm count, and are infertile. Histological examination first detected defects at stage XI of spermatogenesis, when spermatid heads were less elongated. Spermatids were also less numerous than normal, and many shared their cytoplasms and had multiple tails. Of the mutant sperm, 98.5% were nonmotile.

Acridine orange stain revealed defects in chromatin condensation in the sperm heads. \"In order for the sperm to be able to enter the egg, it has to have...a tightly packaged 'hard' head,\" explained Dr. Zhang. \"Given that the sperm head mainly consists of DNA..., it is important that the DNA is tightly condensed by packaging with protamine, instead of histones.\"

Transition nuclear proteins (Tnps) and protamines (Prms) are required for normal chromatin condensation. Using quantitative reverse transcription–polymerase chain reaction (RT-PCR), the investigators found that expression of Tnp1 and Prm1 (genes for transition nuclear protein 1 and protamine 1) was greatly reduced in the spermatids of Jhdm2a knockouts compared with normal mice. A series of analyses support the idea that JHDM2A directly binds to these genes, demethylates their promoter regions, and enables gene expression.

In addition, the expression of Jhdm2a during spermatogenesis increases 70-fold compared with the testes of 7-day-old animals and slightly precedes Tnp1 and Prm2 expression. As Dr. Zhang commented, \"revious studies of Tnp1 and Prm2 knockout mice indicate that both genes are important for spermatogenesis. For sperm maturation, histones are first replaced by Tnps, which are subsequently replaced by Prms. Therefore, both participate sequentially in the same process.\"

Paolo Sassone-Corsi, PhD, distinguished professor and chair, Department of Pharmacology, University of California, Irvine, offered his insights via email about the human implications of the study. \"The abnormalities observed in the Jhdm2a knockout mice are reminiscent of syndromes that are associated with human infertility,\" he observed. Many defects in human germ cell generation occur in the postmeiotic stages, just as in this study.

\"The interesting fact here,\" he continued, \"lies in the role that Jhdm2a has in apparently regulating the specific timing of chromatin remodeling that characterizes the post-histonic transition [after histone replacement by Tnps].\"

Dr. Zhang readily acknowledges that the candidacy of Jhdm2a for human infertility syndromes is only a possibility: \"We do not have any evidence that this indeed is the case,\" he said.

However, Medscape asked Dr. Sassone-Corsi to speculate on what clinical possibilities might open up if Jhdm2a were found to have a role in human infertility: \"A number of possibilities exist.... However, it could be envisaged that by targeting Jhdm2a, and thereby modulating its function, some chromatin remodeling events could be modulated and possibly defects could be corrected.\"

Such targeting would have implications for treating male infertility, but as Dr. Sassone-Corsi reiterated, this \"is far away in time.\"

Dr. Zhang and Dr. Sassone-Corsi have disclosed no relevant financial relationships.