HGNC Approved Gene Symbol: NCOR1
Cytogenetic location: 17p12-p11.2 Genomic coordinates (GRCh38): 17:16,029,157-16,215,534 (from NCBI)
Thyroid hormone receptor (THR1; 190160) and retinoic acid receptor (RARA, 180240; RARB, 180220; RARG, 180190) exert their regulatory functions by acting as both activators and repressors of gene expression. Horlein et al. (1995) identified a mouse cDNA for a nuclear receptor corepressor (Ncor) of relative molecular mass 270,000 that mediates ligand-independent inhibition of gene transcription by Thr1 and Rars. Their finding suggested that the molecular mechanisms of repression by thyroid hormone and retinoic acid receptors are analogous to the corepressor-dependent transcriptional inhibitory mechanisms of yeast and Drosophila. They suggested that the corepressor is a member of a new gene family, which they termed TRAC (thyroid hormone- and retinoic acid receptor-associated corepressor).
Grignani et al. (1998) demonstrated that both PML-RAR-alpha (see 102578) and PLZF-RAR-alpha (see 176797) fusion proteins recruit the NCOR-histone deacetylase (see 601241) complex through the RAR-alpha CoR box. PLZF-RAR-alpha contains a second, retinoic acid-resistant binding site in the PLZF amino-terminal region. High doses of retinoic acid release histone deacetylase activity from PML-RAR-alpha, but not from PLZF-RAR-alpha. Mutation of the NCOR binding site abolishes the ability of PML-RAR-alpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biologic effects of PLZF-RAR-alpha from being an inhibitor to an activator of the retinoic acid signaling pathway. Therefore, Grignani et al. (1998) concluded that recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of retinoic acid on the stability of the PML-RAR-alpha and PLZF-RAR-alpha corepressor complexes determines the differential response of APLs to retinoic acid.
Binding of ligand to nuclear hormone receptors induces a conformation that attracts coactivator proteins containing a Leu-x-x-Leu-Leu motif, the so-called NR box. Hu and Lazar (1999) showed that NCOR1 and SMRT (600848) contain sequences that are similar to the NR box and are repeated in each of 2 nuclear hormone receptor interaction domains. Hu and Lazar (1999) called this box (L/I-x-x-I/V-I) the 'corner box,' or CoRNR box (for 'corepressor/nuclear receptor box'). The CoRNR box is required for nuclear hormone receptor interaction, and the CoRNR box peptides specifically block corepressor interaction in vitro and repression in vivo. Sequences flanking the CoRNR box determine nuclear hormone receptor specificity. Thus, Hu and Lazar (1999) concluded that the key feature of hormone action, differential recognition of unliganded and liganded nuclear hormone receptors by coactivators and corepressors, is due to very subtle differences between CoRNR and NR boxes.
Baek et al. (2002) demonstrated that interleukin-1-beta (IL1B; 147720) causes nuclear export of a specific NCOR corepressor complex, resulting in derepression of a specific subset of nuclear factor-kappa-B (NFKB; see 164011)-regulated genes. These genes are exemplified by the tetraspanin KAI1 (600623), which regulates membrane receptor function. Nuclear export of the NCOR/TAB2 (605101)/HDAC3 (605166) complex by IL1B is temporally linked to selective recruitment of a TIP60 (601409) coactivator complex. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of the beta amyloid precursor protein (APP; 104760), FE65 (602709), and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Zhang et al. (2002) reported that GPS2 (601935), a protein involved in intracellular signaling, is an integral subunit of the NCOR1 NCOR1-HDAC3 complex. They determined structural motifs that direct the formation of a highly stable and active deacetylase complex. GPS2 and TBL1 (300196), another component of the NCOR1-HDAC3 complex, interact cooperatively with repression domain-1 of NCOR1 to form a heterotrimeric structure and are indirectly linked to HDAC3 via an extended NCOR1 SANT domain that also activates latent HDAC3 activity. Zhang et al. (2002) also showed that the NCOR1-HDAC3 complex inhibits JNK (601158) activation through the associated GPS2 subunit and thus could potentially provide an alternative mechanism for hormone-mediated antagonism of AP1 (165160) function.
Yoon et al. (2003) purified NCOR complexes, which contained 10 to 12 proteins, from HeLa cell nuclear extracts and characterized the interactions of TBL1 and TBLR1 (608628) with NCOR. TBL1 and TBLR1 interacted with NCOR through 2 independent interactions. Their N-terminal regions interacted with the RD1 region of NCOR, and their C-terminal WD40 repeats interacted with the RD4 region of NCOR. In vitro, TBL1 and TBLR1 also bound histones H2B (see 609904) and H4 (see 602822), and transcriptional repression by TBL1 and TBLR1 correlated with their interactions with histones. Using small interfering RNAs, Yoon et al. (2003) demonstrated that HDAC3 was essential for repression by unliganded thyroid hormone receptor. TBL1 and TBLR1 were also essential, but they were functionally redundant.
Virtually all neural stem cells maintain an undifferentiated state and the capacity to self-renew in response to fibroblast growth factor-2 (FGF2; 134920). Hermanson et al. (2002) reported that NCOR, a repressor or transcription, is a principal regulator in neural stem cells, since FGF2-treated embryonic cortical progenitors from NCOR gene-disrupted mice displayed impaired self-renewal and spontaneous differentiation into astroglia-like cells. Stimulation of wildtype neural stem cells with ciliary neurotrophic factor (CNTF; 118945), a differentiation-inducing cytokine, resulted in a phosphatidyl-inositol-3-OH kinase/Akt1 kinase-dependent (see 164730) phosphorylation of NCOR, and caused a temporally correlated redistribution of NCOR to the cytoplasm. Hermanson et al. (2002) observed that this is a critical strategy for cytokine-induced astroglia differentiation and lineage-characteristic gene expression. Recruitment of protein phosphatase-1 (see 176875) to a specific binding site on NCOR exerted a reciprocal effect on the cellular localization of NCOR. Hermanson et al. (2002) proposed that repression by NCOR, modulated by opposing enzymatic activities, is a critical mechanism in neural stem cells that underlies the inhibition of glial differentiation.
Using transfected mouse and human cells, Sardi et al. (2006) found that, upon NRG1 (142445)-induced activation and presenilin (PSEN1; 104311)-dependent cleavage of ERBB4 (600543), the ERBB4 intracellular domain formed a complex with TAB2 and NCOR. This complex translocated to the nucleus of undifferentiated rat neural precursors and inhibited their differentiation into astrocytes by repressing transcription of glial genes. Consistent with this observation, cortical astrogenesis occurred precociously in Erbb4-knockout mice, and this phenotype could be rescued by reexpression of a cleavable isoform of human ERBB4, but not by reexpression of an uncleavable ERBB4 isoform.
Using a mapped bacterial artificial chromosome (BAC) containing 158 kb of genomic NCOR1, Ordentlich et al. (1999) mapped the human NCOR1 gene to chromosome 11p11.2.
Jepsen et al. (2000) generated mice with targeted disruption of the Ncor1 gene. Altered patterns of transcription in tissues and cells derived from Ncor1-deficient mice and the resulting block at specific points in central nervous system, erythrocyte, and thymocyte development indicated that NCOR1 is a required component of short-term active repression by nuclear receptors and MAD (600021) and of a subset of long-term repression events mediated by REST (600571). Unexpectedly, NCOR1 and HDAC3 were also required for transcriptional activation of 1 class of retinoic acid response element. Together, these findings suggested that specific combinations of corepressors and histone deacetylases mediate the gene-specific actions of DNA-bound repressors in development of multiple organ systems.
Alenghat et al. (2008) created a knockin mouse model in which a missense mutation, Y478A, was introduced into the Ncor1 deacetylase activation domain (DAD). This created a mutant protein that was stable but unable to associate with or activate Hdac3. The DADm mice were viable, born at normal mendelian frequencies, and morphologically indistinguishable from wildtype littermates at birth. Thus, Ncor1 binding to Hdac3 is not required for normal development, and the embryonic defects of mice lacking Ncor1 are due to factors other than, or in addition to, Hdac3 recruitment by Ncor1. However, the DADm mice had aberrant regulation of clock genes and had abnormal circadian behavior. These mice were leaner and more insulin-sensitive owing to increased energy expenditure. Unexpectedly, loss of a functional Ncor1-Hdac3 complex in vivo did not lead to sustained increases in known catabolic genes, but instead significantly altered the oscillatory patterns of several metabolic genes, demonstrating that circadian regulation of metabolism is critical for normal energy balance. Alenghat et al. (2008) concluded that activation of Hdac3 by Ncor1 is a nodal point in the epigenetic regulation of circadian and metabolic physiology.
Alenghat, T., Meyers, K., Mullican, S. E., Leitner, K., Adeniji-Adele, A., Avila, J., Bucan, M., Ahima, R. S., Kaestner, K. H., Lazar, M. A. Nuclear receptor corepressor and histone deacetylase 3 govern circadian metabolic physiology. Nature 456: 997-1000, 2008. [PubMed: 19037247] [Full Text: https://doi.org/10.1038/nature07541]
Baek, S. H., Ohgi, K. A., Rose, D. W., Koo, E. H., Glass, C. K., Rosenfeld, M. G. Exchange of N-CoR corepressor and Tip60 coactivator complexes links gene expression by NF-kappa-B and beta-amyloid precursor protein. Cell 110: 55-67, 2002. [PubMed: 12150997] [Full Text: https://doi.org/10.1016/s0092-8674(02)00809-7]
Grignani, F., De Matteis, S., Nervi, C., Tomassoni, L., Gelmetti, V., Cioce, M., Fanelli, M., Ruthardt, M., Ferrara, F. F., Zamir, I., Seiser, C., Grignani, F., Lazar, M. A., Minucci, S., Pelicci, P. G. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391: 815-818, 1998. [PubMed: 9486655] [Full Text: https://doi.org/10.1038/35901]
Hermanson, O., Jepsen, K., Rosenfeld, M. G. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419: 934-939, 2002. [PubMed: 12410313] [Full Text: https://doi.org/10.1038/nature01156]
Horlein, A. J., Naar, A. M., Heinzel, T., Torchia, J., Gloss, B., Kurokawa, R., Ryan, A., Kamel, Y., Soderstrom, M., Glass, C. K., Rosenfeld, M. G. Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377: 397-403, 1995. [PubMed: 7566114] [Full Text: https://doi.org/10.1038/377397a0]
Hu, X., Lazar, M. A. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature 402: 93-96, 1999. [PubMed: 10573424] [Full Text: https://doi.org/10.1038/47069]
Jepsen, K., Hermanson, O., Onami, T. M., Gleiberman, A. S., Lunyak, V., McEvilly, R. J., Kurokawa, R., Kumar, V., Liu, F., Seto, E., Hedrick, S. M., Mandel, G., Glass, C. K., Rose, D. W., Rosenfeld, M. G. Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102: 753-763, 2000. [PubMed: 11030619] [Full Text: https://doi.org/10.1016/s0092-8674(00)00064-7]
Ordentlich, P., Downes, M., Xie, W., Genin, A., Spinner, N. B., Evans, R. M. Unique forms of human and mouse nuclear receptor corepressor SMRT. Proc. Nat. Acad. Sci. 96: 2639-2644, 1999. [PubMed: 10077563] [Full Text: https://doi.org/10.1073/pnas.96.6.2639]
Sardi, S. P., Murtie, J., Koirala, S., Patten, B. A., Corfas, G. Presenilin-dependent ErbB4 nuclear signaling regulates the timing of astrogenesis in the developing brain. Cell 127: 185-197, 2006. [PubMed: 17018285] [Full Text: https://doi.org/10.1016/j.cell.2006.07.037]
Yoon, H.-G., Chan, D. W., Huang, Z.-Q., Li, J., Fondell, J. D., Qin, J., Wong, J. Purification and functional characterization of the human N-CoR complex: the roles of HDAC3, TBL1 and TBLR1. EMBO J. 22: 1336-1346, 2003. [PubMed: 12628926] [Full Text: https://doi.org/10.1093/emboj/cdg120]
Zhang, J., Kalkum, M., Chait, B. T., Roeder, R. G. The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2. Molec. Cell 9: 611-623, 2002. [PubMed: 11931768] [Full Text: https://doi.org/10.1016/s1097-2765(02)00468-9]