Alternative titles; symbols
HGNC Approved Gene Symbol: HOPX
Cytogenetic location: 4q12 Genomic coordinates (GRCh38) : 4:56,647,998-56,681,706 (from NCBI)
By searching an EST database using the PAX3 (606597) homeodomain as probe, Chen et al. (2002) identified mouse Hop. They identified human HOP by further EST database searching. The human and mouse proteins contain 73 amino acids, including a 60-amino acid motif homologous to HOX proteins, and share 92% identity. They are most closely related to the homeodomain proteins HOX6 and goosecoid (138890), with approximately 40% identity within the homeodomain-like domain. HOP lacks certain conserved residues required for DNA binding. In mouse, Hop gene expression initiates early in cardiogenesis and continues in cardiomyocytes throughout embryonic and postnatal development. Northern blot analysis of adult and embryonic mouse tissues detected a 1.2-kb transcript in embryonic and adult heart and in adult brain, intestine, and spleen. Immunohistochemistry confirmed that Hop is a nuclear protein.
Shin et al. (2002) independently cloned mouse Hop and identified the human homolog. They determined that Hop forms 3 alpha helices with a helix-turn-helix motif characteristic of the homeodomain. Northern blot analysis of mouse tissues detected a 1.3-kb transcript in heart, lung, brain, and liver. Hop was highly expressed in developing heart, where its expression was dependent on the cardiac-restricted homeodomain protein Nkx2.5 (CSX; 600584).
Genetic and biochemical data indicated to Chen et al. (2002) that mouse Hop functions directly downstream of Nkx2.5. They showed that Hop physically interacts with serum response factor (SRF; 600589) and inhibits activation of SRF-dependent transcription by inhibiting SRF binding to DNA. Chen et al. (2002) concluded that HOP is an unusual homeodomain protein that modulates SRF-dependent, cardiac-specific gene expression and cardiac development.
Shin et al. (2002) confirmed that mouse Hop does not bind DNA and acts as an antagonist of SRF, which regulates the opposing processes of proliferation and myogenesis.
By yeast 2-hybrid analysis, Kee et al. (2007) found that HOP interacted with EPC1 (610999). Expression of Epc1 was upregulated during differentiation of a rat myoblast cell line into skeletal myocytes. Differentiation was induced by Epc1 overexpression and was severely impaired in Epc1-knockdown cells. Cotransfection of Hop potentiated Epc1-induced transactivation of myogenin (MYOG; 159980) and myotube formation. Skeletal muscle of Hop-knockout mice showed decreased expression of myosin heavy chain (see 160730) and myogenin, and hamstring muscle of Hop-knockout mice showed delayed healing after injury. Differentiation was impaired in skeletal myoblasts from Hop-knockout mice. Kee et al. (2007) concluded that EPC1 plays a role in initiation of skeletal muscle differentiation and that its interaction with HOP is required for full activity.
Jain et al. (2015) compared lineage tracing of multipotent cardiac progenitor cells marked by Islet1 (600366) and Nkx2-5 (600584) expression with lineage tracing of Hopx+ cells. Jain et al. (2015) defined and characterized a Hopx-expressing cardiomyoblast intermediate that is committed to the cardiomyocyte fate. Hopx is initially expressed in a subset of cardiac progenitor cells residing in the precardiac mesoderm prior to the expression of troponin T (TNNT2; 191045). Lineage-tracing experiments demonstrated that Hopx+ cells give rise to cardiac myocytes exclusively. Whole-genome analysis revealed that Hopx occupies regulatory regions of multiple Wnt-related genes, and Hopx-null cardiac tissues are characterized by an expansion of Wnt signaling. Restoration of Wnt levels during differentiation of Hopx-null embryoid bodies partially rescued myogenesis.
The International Radiation Hybrid Mapping Consortium mapped the HOP gene to chromosome 4 (WI-6363).
Chen et al. (2002) found that inactivation of Hop in mice by homologous recombination resulted in a partially penetrant embryonic lethal phenotype with severe developmental cardiac defects involving the myocardium. Inhibition of Hop activity in zebrafish embryos likewise disrupted cardiac development and resulted in severely impaired cardiac function.
Shin et al. (2002) showed that mice homozygous for a Hop null allele segregated into 2 phenotypic classes characterized by an excess or deficiency of cardiac myocytes. They proposed that Hop modulates SRF activity during heart development and that its absence results in an imbalance between cardiomyocyte proliferation and differentiation, with consequent abnormalities in cardiac morphogenesis.
Using transgenic mice in which Hop was expressed in the heart under the control of the alpha-MHC promoter, Kook et al. (2003) showed that Hop can inhibit SRF-dependent transcriptional activation by recruiting histone deacetylase (HDAC; see 601241) activity and can form a complex that includes HDAC2 (605164). Transgenic mice overexpressing Hop developed severe cardiac hypertrophy, cardiac fibrosis, and premature death. A mutant form of Hop, which does not recruit HDAC activity, did not induce hypertrophy. Treatment of Hop transgenic mice with trichostatin A, an HDAC inhibitor, prevented hypertrophy. Kook et al. (2003) concluded that chromatin remodeling and repression of otherwise active transcriptional processes can result in hypertrophy and heart failure, and that this process can be blocked with chemical HDAC inhibitors.
Chen, F., Kook, H., Milewski, R., Gitler, A. D., Milewski, R., Gitler, A. D., Lu, M. M., Li, J., Nazarian, R., Schnepp, R., Jen, K., Biben, C., Runke, G., Mackay, J. P., Novotny, J., Schwartz, R. J., Harvey, R. P., Mullins, M. C., Epstein, J. A. Hop is an unusual homeobox gene that modulates cardiac development. Cell 110: 713-723, 2002. [PubMed: 12297045] [Full Text: https://doi.org/10.1016/s0092-8674(02)00932-7]
Jain, R., Li, D., Gupta, M., Manderfield, L. J., Ifkovits, J. L., Wang, Q., Liu, F., Liu, Y., Poleshko, A., Padmanabhan, A., Raum, J. C., Li, L., Morrisey, E. E., Lu, M. M., Won, K.-J., Epstein, J. A. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Science 348: 1444 only, 2015.
Kee, H. J., Kim, J.-R., Nam, K.-I., Park, H. Y., Shin, S., Kim, J. C., Shimono, Y., Takahashi, M., Jeong, M. H., Kim, N., Kim, K. K., Kook, H. Enhancer of polycomb1, a novel homeodomain only protein-binding partner, induces skeletal muscle differentiation. J. Biol. Chem. 282: 7700-7709, 2007. [PubMed: 17192267] [Full Text: https://doi.org/10.1074/jbc.M611198200]
Kook, H., Lepore, J. J., Gitler, A. D., Lu, M. M., Yung, W. W.-M., Mackay, J., Zhou, R., Ferrari, V., Gruber, P., Epstein, J. A. Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J. Clin. Invest. 112: 863-871, 2003. [PubMed: 12975471] [Full Text: https://doi.org/10.1172/JCI19137]
Shin, C. H., Liu, Z.-P., Passier, R., Zhang, C.-L., Wang, D.-Z., Harris, T. M., Yamagishi, H., Richardson, J. A., Childs, G., Olson, E. N. Modulation of cardiac growth and development by HOP, an unusual homeodomain protein. Cell 110: 725-735, 2002. [PubMed: 12297046] [Full Text: https://doi.org/10.1016/s0092-8674(02)00933-9]