Molecular Characterization of Heat Shock-Like Factor Encoded on the Human Y Chromosome, and Implications for Male Infertility1

Abstract

Azoospermia and oligospermia are major causes of male infertility. Some genes located on the Y chromosome are suggested as candidates. Recently, HSFY, which is similar to the HSF (heat shock transcription factor) family, has been mapped on the human Y chromosome as multicopies. However, newly available sequence data deposited at NCBI shows that only the HSFY gene located on Yq has a long open reading frame containing a HSF-type DNA-binding domain. HSFY is similar to LW-1 on the human X chromosome and a murine HSFY-like sequence (mHSFYL), 4933413G11Rik, on the mouse chromosome 1. LW-1 and mHSFYL have 53% and 70% homology to HSFY for amino acid sequences of their presumed DNA-binding domains, respectively. Comparison of the presumed DNA-binding domains unveiled that the three HSF-like factors, HSFY, LW-1, and mHSFYL, belong to a different class than conventional HSFs. When we screened for deletions on the Yq of males suffering from infertility, we found that HSFY was involved in interstitial deletions on the Y chromosomes for two azoospermic males who had DBY, USP9Y, and DAZ but did not have RBMY located on the AZFb. Expression analysis of HSFY, LW-1, and mHSFYL unveiled that they are expressed predominantly in testis. Furthermore, immunhistochemistry of HSFY in testis showed that its expression is restricted to both Sertoli cells and spermatogenic cells and that it exhibits a stage-dependent translocation from the cytoplasm to the nucleus in spermatogenetic cells during spermatogenesis. These results may suggest that deletion of HSFY is involved in azoospermia or oligospermia.

Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

“…Though the function of HSFY is not presently understood, it is expressed in human germ cells and Sertoli cells 28 and likely acts by moderating expression of heat-shock proteins, which serve as important transcription factors. The DNA binding capacity of HSFY protein suggests a regulatory role for this gene during spermiogenesis.…”

Y chromosome and male infertility: Update, 2006

“…This gene encodes a novel heat shock protein which is specifically expressed in Sertoli and germ cells which exhibits a stagedependent translocation from the cytoplasm to the nucleus in spermatogenic cells during spermatogenesis (32). The gene has a homologue HSP2 on 6p22 which codes for a heat shock transcription factor.…”

Spermatocyte-specific expression of constitutively active heat shock factor 1 induces HSP70i-resistant apoptosis in male germ cells

“…More recently, HSF-similar factor HSFY, which is expressed predominantly in testis, has been discovered. 32,33 Under physiological conditions HSF1 exists as an inactive monomer, while trimerization of HSF1 takes place in response to cellular stress and the trimer binds cisacting DNA sequences termed heat shock elements (HSEs) (reviewed in Fernandes et al 34 ). Activation-induced oligomerization of HSF1 is controlled by intra-and intermolecular hydrophobic interactions mediated by several conserved repeated motifs.…”