Alternative titles; symbols
HGNC Approved Gene Symbol: HSF2
Cytogenetic location: 6q22.31 Genomic coordinates (GRCh38): 6:122,399,551-122,433,119 (from NCBI)
Heat-shock transcription factors activate heat-shock response genes under conditions of heat or other stresses. Using the partial peptide sequence of HSF1 (140580) from HeLa cells to screen a human T-cell cDNA library, Schuetz et al. (1991) isolated HSF2. HSF1 and HSF2 encode proteins that bind specifically to the heat-shock element and have homology to HSFs of other species. Schuetz (1991) pointed out that although the names HSF1 and HSF2 were chosen for historical reasons, these peptides should be referred to as heat-shock transcription factors.
Kallio et al. (2002) found that mouse Hsf2 was expressed in all 3 embryonic layers at embryonic day 7.5 and that the head fold was strongly stained at embryonic day 8.5. At later developmental stages, Hsf2 expression was progressively limited to the central nervous system. In adults, Hsf2 expression was detected in spermatocytes and spermatogonia, but not in elongated spermatids, spermatozoa, or Sertoli cells.
Stumpf (2023) mapped the HSF2 gene to chromosome 6q22.31 based on an alignment of the HSF2 sequence (GenBank BC128420) with the genomic sequence (GRCh38).
In contrast to most genomic DNA in mitotic cells, the promoter regions of some genes, such as the stress-inducible hsp70i gene that codes for a heat-shock protein, remain uncompacted, a phenomenon known as bookmarking. Xing et al. (2005) showed that hsp70i bookmarking is mediated by a transcription factor called HSF2, which binds this promoter in mitotic cells, recruits protein phosphatase-2A (see 605997), and interacts with the CAPG subunit of the condensin enzyme (606280) to promote efficient dephosphorylation and inactivation of condensin complexes in the vicinity, thereby preventing compaction at this site. Blocking HSF2-mediated bookmarking by HSF2 RNA interference decreased hsp70i induction and survival of stressed cells in the G1 phase. Xing et al. (2005) concluded that this demonstrated the biologic importance of gene bookmarking.
For discussion of a possible association between spermatogenic failure (see 258150) and mutation in the HSF2 gene, see 140581.0001.
Kallio et al. (2002) found that Hsf2-null mice were born at the expected mendelian ratio but had brain abnormalities and meiotic and gametogenic defects in both genders. Enlargement of the lateral and third ventricles and reduction of the hippocampus and striatum correlated with Hsf2 expression in proliferative cells of the neuroepithelium and in some ependymal cells in adults. In Hsf2-null males, many developing spermatocytes were eliminated via apoptosis in a stage-specific manner, and pachytene spermatocytes displayed structural defects in the synaptonemal complexes between homologous chromosomes. In Hsf2-null females, abnormal egg production, reduced ovarian follicle number, and hemorrhagic cystic follicles were consistent with meiotic defects. Hsf2-null females also showed hormone response defects that could be rescued by superovulation treatment, and they showed abnormal luteinizing hormone receptor mRNA (152790) levels.
This variant is classified as a variant of unknown significance because its contribution to spermatogenic failure (see 258150) has not been confirmed.
Mou et al. (2013) screened for exonic mutations in the candidate gene HSF2 in 766 Chinese men with azoospermic infertility and 521 men with proven fertility, and identified 1 man with a heterozygous missense mutation, a c.1505G-A transition resulting in an arg502-to-his (R502H) substitution at a highly conserved residue. The mutation was not found in the fertile controls or in the dbSNP (build 135) or 1000 Genomes Project databases. Functional analysis in HeLa and 293FT cell lines demonstrated that in contrast to wildtype HSF2, the mutant failed to activate the HSPA2 (140560) promoter. Coexpression analysis demonstrated that the R502H mutant inhibited the transcriptional regulatory activity of the wildtype allele through a dominant-negative effect. Testicular biopsy from the patient carrying the heterozygous variant confirmed the diagnosis of nonobstructive azoospermia, and showed blockage of the spermatogenic process primarily at the spermatocyte stage. Mou et al. (2013) concluded that their findings supported a role for HSF2 in the pathogenesis of idiopathic azoospermia.
Kallio, M., Chang, Y., Manuel, M., Alastalo, T.-P., Rallu, M., Gitton, Y., Pirkkala, L., Loones, M.-T., Paslaru, L., Larney, S., Hiard, S., Morange, M., Sistonen, L., Mezger, V. Brain abnormalities, defective meiotic chromosome synapsis and female subfertility in HSF2 null mice. EMBO J. 21: 2591-2601, 2002. [PubMed: 12032072] [Full Text: https://doi.org/10.1093/emboj/21.11.2591]
Mou, L., Wang, Y., Li, H., Huang, Y., Jiang, T., Huang, W., Li, Z., Chen, J., Xie, J., Liu, Y., Jiang, Z., Li, X., Ye, J., Cai, Z., Gui, Y. A dominant-negative mutation of HSF2 associated with idiopathic azoospermia. Hum. Genet. 132: 159-165, 2013. [PubMed: 23064888] [Full Text: https://doi.org/10.1007/s00439-012-1234-7]
Schuetz, T. J., Gallo, G. J., Sheldon, L., Tempst, P., Kingston, R. E. Isolation of a cDNA for HSF2: evidence for two heat shock factor genes in humans. Proc. Nat. Acad. Sci. 88: 6911-6915, 1991. [PubMed: 1871106] [Full Text: https://doi.org/10.1073/pnas.88.16.6911]
Schuetz, T. J. Personal Communication. Boston, Mass. 10/3/1991.
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/25/2023.
Xing, H., Wilkerson, D. C., Mayhew, C. N., Lubert, E. J., Skaggs, H. S., Goodson, M. L., Hong, Y., Park-Sarge, O.-K., Sarge, K. D. Mechanism of hsp70i gene bookmarking. Science 307: 421-423, 2005. [PubMed: 15662014] [Full Text: https://doi.org/10.1126/science.1106478]