Kevin Ryan

Biology 303

November 8, 2007

An Analysis of the CoREST-CtBP Co-repressor Complex

Histone deacetylases (HDACs) are defined as a class of enzymes that remove acetyl groups on a histone, causing the histones to wrap more tightly around the DNA and interfering with gene transcription. CoREST, part of a CtBP complex, has been identified as a HDAC. Additionally, CoREST is recruited by many transcription factors, including REST, to initiate co-repression. LSD1, a histone lysine demethylase, is contained within the CoREST-CtBP complex and acts as a gene activator. Furthermore, the CtBP complex has been shown to have important properties in histone modification. For these reasons, the CoREST-CtBP co-repressor complex must be identified as an important HDAC.

CoREST was originally classified as a human protein that acts as a corepressor for REST, or RE1 silencing transcription factor. “Together, REST and CoREST mediate repression of the type II sodium channel promoter in nonneural cells, and the REST / CoREST complex may mediate long-term repression essential to maintenance of cell identity.” (Andres, et al., 9873) REST contains two domains that are required for full repression of the sodium channels. These two domains are the amino and carboxyl termini. Only one domain is needed to initiate repression. CoREST connects to REST at the carboxyl domain, due to the presence of C-terminal binding protein (CtBP). The specificity of CoREST’s attachment to REST was determined through a point mutation. “Furthermore, a point mutation in the zinc-finger motif that abolished repression also abolished the REST-CoREST interaction.” (Andres, et al., 9876) The binding of REST-CoREST to repress sodium channels confirms the presence of a CtBP on Co-REST and also the ability of Co-REST to interfere with gene transcription. (Andres, et al.)

The two repression domains of REST are an N-terminal domain that recruits the mSin3 HDAC complex and a C-terminal domain that recruits CoREST. Because REST can be activated through either domain, CoREST must be considered a HDAC itself. “CoREST-HDAC is composed of polypeptides distinct from previously characterized HDAC 1/2-containing complexes such as the mSin3.” (You, et al., 1454) The HDAC 1 / 2 connected to CoREST lacks RbAp46 and RbAp48, even though these proteins have been found on all previous complexes containing HDAC 1 / 2. This discovery leads to the belief that CoREST is a HDAC complex within itself. “Although CoREST first was identified as a REST-interacting protein, we believe that CoREST forms a stable histone deacetylase complex that is recruited by transcription factors, of which REST is perhaps one of many.” (You, et al., 1457)

LSD1, histone lysine demethylase, is located on the CoREST-CtBP complex and is required for full development in the pituitary gland during metazoan growth. The use of LSD1 in pituitary development magnifies the importance of Co-REST HDAC apart from its use with REST. LSD1 is not involved in direct growth of the pituitary, but rather represses the expression of certain hormones in the pituitary gland. “Thus, LSD1 controls late cell-lineage determination and terminal differentiation events but not early cell-lineage commitment events during pituitary development, indicating specificity of LSD1 in transcriptional control.” (Wang, et al., 883) The discovery of LSD1 helps to clarify the role of the CoREST-CtBP complex throughout the body. In the pituitary, LSD1 controls transcription in late-cell determination and additionally regulates gene activation and repression. “…suggesting that LSD1 is temporally and spatially positioned to exert critical roles in specific gene activation programmes…During pituitary development, LSD1 seems to regulate, directly or indirectly, gene repression programmes as well.” (Wang, 883) LSD1 was found to activate expression of Pit1 cells and repression of Hey1 cells in the pituitary. Pit1 is a critical transcription factor for gene expression and Hey1, part of a Notch-signalled pathway, acts as a promoter. LSD1 regulates gene expression during pituitary organogenesis by activating expression of Pit1 and by repression of Hey1 through a critical role in CtBP-mediated repression of Notch signaling.

C-terminal binding protein, CtBP, acts as an important part of the CoREST-CtBP complex because it is actively recruited by transcription factors. CtBP both targets genes and coordinates histone modification. CoREST combines with CtBP to present an effective corepressor. “The presence of CoREST and its associated proteins in the CtBP complex suggests a possible interplay between these two co-repressors.” (Shi, et al., 735) CtBP acts a repressor in conjunction with HDAC 1 / 2. Shi, et al. found that several proteins, including CtBP 1 and 2, HDAC2 and CoREST are components of the entire CtBP complex. CtBP’s role in repression is important because further study may lead to interesting revelations concerning cancer treatment. “Biologically, the identification of the proteins involved in tumorigenesis in the CtBP complex, and the finding that CtBP and the associated HMTs repress transcription of the tumour invasion suppressor E-cad, sheds significant lights on the role of CtBP in tumorigenesis.” (Shi, et al., 737) Manipulation of the CoREST-CtBP complex may lead to repression of tumorigenesis. Because of its use as a binding site and its importance in tumorigenesis, CtBP must be considered an important part of the CoREST-CtBP complex. (Shi, et al.)

The CoREST-CtBP complex has been proven to be an important HDAC. Its involvement in gene transcription throughout the body is varied. CoREST itself acts as a corepressor with REST, amongst other chores. LSD1, an important component of the complex, is necessary for full formation of the pituitary gland. Additionally, CtBP acts as an important factor in tumorigenesis and helps CoREST to bind with REST during sodium channel repression. Because of these reasons, continued research of the CoREST-CtBP complex is necessary to determine its further roles throughout the body and how this complex may be manipulated to express certain traits.


References

Andres, Maria, et al. “CoREST: A functional corepressor required for regulation of

neural-specific gene expression.” PNAS 96 (1999): 9873-9878

Shi, Yujiang, et al. “Coordinated histone modifications mediated by a CtBP co-repressor

complex.” Nature 422 (2003): 735-738

Wang, Jianxun, et al. “Opposing LSD1 complexes function in developmental gene

activation and repression programmes.” Nature 446 (2007): 882-887

You, Angei, et al. “CoREST is an integral component of the CoREST-human histone

deacetylase complex.” PNAS 98 (2000): 1454-1458