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Redundant or separate entities?--roles of Twist1 and Twist2 as molecular switches during gene transcription.

Franco HL, Casasnovas J, Rodríguez-Medina JR, Cadilla CL - Nucleic Acids Res. (2010)

Bottom Line: Regulatory outcomes of Twist1 and Twist2 are themselves controlled by spatial-temporal expression, phosphoregulation, dimer choice and cellular localization.Although these two proteins are highly conserved and exhibit similar functions in vitro, emerging literature have demonstrated different roles in vivo.The involvement of Twist1 and Twist2 in a broad spectrum of regulatory pathways highlights the importance of understanding their roles in normal development, homeostasis and disease.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Lab, Department of Biochemistry, School of Medicine University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936, USA.

ABSTRACT
Twist1 and Twist2 are highly conserved members of the Twist subfamily of bHLH proteins responsible for the transcriptional regulation of the developmental programs in mesenchymal cell lineages. The regulation of such processes requires that Twist1 and Twist2 function as molecular switches to activate and repress target genes by employing several direct and indirect mechanisms. Modes of action by these proteins include direct DNA binding to conserved E-box sequences and recruitment of coactivators or repressors, sequestration of E-protein modulators, and interruption of proper activator/repressor function through protein-protein interactions. Regulatory outcomes of Twist1 and Twist2 are themselves controlled by spatial-temporal expression, phosphoregulation, dimer choice and cellular localization. Although these two proteins are highly conserved and exhibit similar functions in vitro, emerging literature have demonstrated different roles in vivo. The involvement of Twist1 and Twist2 in a broad spectrum of regulatory pathways highlights the importance of understanding their roles in normal development, homeostasis and disease. Here we focus on the mechanistic models of transcriptional regulation and summarize the similarities and differences between Twist1 and Twist2 in the context of myogenesis, osteogenesis, immune system development and cancer.

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Related in: MedlinePlus

Modes of transcriptional regulation by Twist1 and Twist2. The Twist1 (TW1) and Twist2 (TW2) bHLH transcription factors exhibit a bifunctional role by acting as activators and repressors depending on post-translational modifications, partner choice and cellular context (6,7,28). (A) The mode of action employed by Twist1 and Twist2 was first understood in genes involved in muscle development. The myogenic bHLH factors such as MyoD bind as heterodimers with E-proteins to E-boxes found in regulatory regions of muscle-specific genes. MyoD-mediated activation typically requires the binding of MEF2 and involves the recruitment of HATs. Twist acts as a repressor by promoting deacetylation either by blocking HAT activity or recruiting HDACs (35,38). (B) The role of Twist during osteogenesis was highlighted when mutations of Twist1 were identified in SCS patients. Based on the SCS mouse model and studies in human osteoblasts, it was determined that Twist1 acted before Twist2 on osteoblast maturation (20,23). Twist1, as a heterodimer with E12, represses the FGFR2 gene, and as Id protein levels rise, E12 gets sequestered leading to Twist1 homodimerization. As a homodimer, Twist1 activates FGFR2 which mediates downstream activation of RunX2 (26,42). Aside of FGF signaling, both Twist1 and Twist2 can block the transactivation activity of the master regulator RunX2 (25). (C) Twist can repress genes independent of DNA binding. For example, Twist can sequester E12 or MyoD leading to the repression genes of the myogenic program. By doing so, Twist mimics the mechanism of inhibition employed by the Id proteins. (D) Twist partner choice can be determined by the phosphorylation state of these proteins leading to homodimerization, or heterodimerization with Class A and Class B bHLH factors. E-box selection can also be influenced by phosphoregulation. In this case, affinity for a class B bHLH factor, Hand2, is favored when Twist1 is phosphorylated by PKA (29,31). (E) The Twist2 KO mouse suggests a role of Twist2 in regulating cytokine gene expression (22). This work lead to a proposed negative feedback loop in which inflammatory cytokines activate NF-kB, and NF-kB activates the expression of cytokines and both Twist1 and Twist2. In turn, Twist1 and Twist2 can block the transactivation activity of NF-kB in a promoter-specific matter (45).
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Figure 2: Modes of transcriptional regulation by Twist1 and Twist2. The Twist1 (TW1) and Twist2 (TW2) bHLH transcription factors exhibit a bifunctional role by acting as activators and repressors depending on post-translational modifications, partner choice and cellular context (6,7,28). (A) The mode of action employed by Twist1 and Twist2 was first understood in genes involved in muscle development. The myogenic bHLH factors such as MyoD bind as heterodimers with E-proteins to E-boxes found in regulatory regions of muscle-specific genes. MyoD-mediated activation typically requires the binding of MEF2 and involves the recruitment of HATs. Twist acts as a repressor by promoting deacetylation either by blocking HAT activity or recruiting HDACs (35,38). (B) The role of Twist during osteogenesis was highlighted when mutations of Twist1 were identified in SCS patients. Based on the SCS mouse model and studies in human osteoblasts, it was determined that Twist1 acted before Twist2 on osteoblast maturation (20,23). Twist1, as a heterodimer with E12, represses the FGFR2 gene, and as Id protein levels rise, E12 gets sequestered leading to Twist1 homodimerization. As a homodimer, Twist1 activates FGFR2 which mediates downstream activation of RunX2 (26,42). Aside of FGF signaling, both Twist1 and Twist2 can block the transactivation activity of the master regulator RunX2 (25). (C) Twist can repress genes independent of DNA binding. For example, Twist can sequester E12 or MyoD leading to the repression genes of the myogenic program. By doing so, Twist mimics the mechanism of inhibition employed by the Id proteins. (D) Twist partner choice can be determined by the phosphorylation state of these proteins leading to homodimerization, or heterodimerization with Class A and Class B bHLH factors. E-box selection can also be influenced by phosphoregulation. In this case, affinity for a class B bHLH factor, Hand2, is favored when Twist1 is phosphorylated by PKA (29,31). (E) The Twist2 KO mouse suggests a role of Twist2 in regulating cytokine gene expression (22). This work lead to a proposed negative feedback loop in which inflammatory cytokines activate NF-kB, and NF-kB activates the expression of cytokines and both Twist1 and Twist2. In turn, Twist1 and Twist2 can block the transactivation activity of NF-kB in a promoter-specific matter (45).

Mentions: There are several factors that influence the function of Twist1 and Twist2. These include dimer choice, phosphoregulation, protein–protein interactions and spatial-temporal expression. Dimer choice is mainly influenced by the availability of other bHLH proteins within the cell and the phosphorylation state of these proteins (26–28). It is known that Class B bHLH factors can form functional homodimers as well as heterodimers with Class A bHLH factors including E12/E47. However, heterodimer formation among class B bHLH proteins has also been reported as in the case with Twist1 and Hand2 dimer formation (Figure 2D) (6,29). Id proteins have great affinity for E12 and compete against class B bHLH proteins for E12 binding (26,28,30). Therefore, Id proteins actively alter dimerization pools by binding and sequestering bHLH factors, without themselves being able to bind DNA. The composition of these partner pools will ultimately determine the expression profile and therefore the cellular response. Hence, the relative stoichiometry of these factors influence whether Twist1 or Twist2 form heterodimers with E12, or homodimer formation is favored due to Id-mediated E12 sequestration.Figure 2.


Redundant or separate entities?--roles of Twist1 and Twist2 as molecular switches during gene transcription.

Franco HL, Casasnovas J, Rodríguez-Medina JR, Cadilla CL - Nucleic Acids Res. (2010)

Modes of transcriptional regulation by Twist1 and Twist2. The Twist1 (TW1) and Twist2 (TW2) bHLH transcription factors exhibit a bifunctional role by acting as activators and repressors depending on post-translational modifications, partner choice and cellular context (6,7,28). (A) The mode of action employed by Twist1 and Twist2 was first understood in genes involved in muscle development. The myogenic bHLH factors such as MyoD bind as heterodimers with E-proteins to E-boxes found in regulatory regions of muscle-specific genes. MyoD-mediated activation typically requires the binding of MEF2 and involves the recruitment of HATs. Twist acts as a repressor by promoting deacetylation either by blocking HAT activity or recruiting HDACs (35,38). (B) The role of Twist during osteogenesis was highlighted when mutations of Twist1 were identified in SCS patients. Based on the SCS mouse model and studies in human osteoblasts, it was determined that Twist1 acted before Twist2 on osteoblast maturation (20,23). Twist1, as a heterodimer with E12, represses the FGFR2 gene, and as Id protein levels rise, E12 gets sequestered leading to Twist1 homodimerization. As a homodimer, Twist1 activates FGFR2 which mediates downstream activation of RunX2 (26,42). Aside of FGF signaling, both Twist1 and Twist2 can block the transactivation activity of the master regulator RunX2 (25). (C) Twist can repress genes independent of DNA binding. For example, Twist can sequester E12 or MyoD leading to the repression genes of the myogenic program. By doing so, Twist mimics the mechanism of inhibition employed by the Id proteins. (D) Twist partner choice can be determined by the phosphorylation state of these proteins leading to homodimerization, or heterodimerization with Class A and Class B bHLH factors. E-box selection can also be influenced by phosphoregulation. In this case, affinity for a class B bHLH factor, Hand2, is favored when Twist1 is phosphorylated by PKA (29,31). (E) The Twist2 KO mouse suggests a role of Twist2 in regulating cytokine gene expression (22). This work lead to a proposed negative feedback loop in which inflammatory cytokines activate NF-kB, and NF-kB activates the expression of cytokines and both Twist1 and Twist2. In turn, Twist1 and Twist2 can block the transactivation activity of NF-kB in a promoter-specific matter (45).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3045590&req=5

Figure 2: Modes of transcriptional regulation by Twist1 and Twist2. The Twist1 (TW1) and Twist2 (TW2) bHLH transcription factors exhibit a bifunctional role by acting as activators and repressors depending on post-translational modifications, partner choice and cellular context (6,7,28). (A) The mode of action employed by Twist1 and Twist2 was first understood in genes involved in muscle development. The myogenic bHLH factors such as MyoD bind as heterodimers with E-proteins to E-boxes found in regulatory regions of muscle-specific genes. MyoD-mediated activation typically requires the binding of MEF2 and involves the recruitment of HATs. Twist acts as a repressor by promoting deacetylation either by blocking HAT activity or recruiting HDACs (35,38). (B) The role of Twist during osteogenesis was highlighted when mutations of Twist1 were identified in SCS patients. Based on the SCS mouse model and studies in human osteoblasts, it was determined that Twist1 acted before Twist2 on osteoblast maturation (20,23). Twist1, as a heterodimer with E12, represses the FGFR2 gene, and as Id protein levels rise, E12 gets sequestered leading to Twist1 homodimerization. As a homodimer, Twist1 activates FGFR2 which mediates downstream activation of RunX2 (26,42). Aside of FGF signaling, both Twist1 and Twist2 can block the transactivation activity of the master regulator RunX2 (25). (C) Twist can repress genes independent of DNA binding. For example, Twist can sequester E12 or MyoD leading to the repression genes of the myogenic program. By doing so, Twist mimics the mechanism of inhibition employed by the Id proteins. (D) Twist partner choice can be determined by the phosphorylation state of these proteins leading to homodimerization, or heterodimerization with Class A and Class B bHLH factors. E-box selection can also be influenced by phosphoregulation. In this case, affinity for a class B bHLH factor, Hand2, is favored when Twist1 is phosphorylated by PKA (29,31). (E) The Twist2 KO mouse suggests a role of Twist2 in regulating cytokine gene expression (22). This work lead to a proposed negative feedback loop in which inflammatory cytokines activate NF-kB, and NF-kB activates the expression of cytokines and both Twist1 and Twist2. In turn, Twist1 and Twist2 can block the transactivation activity of NF-kB in a promoter-specific matter (45).
Mentions: There are several factors that influence the function of Twist1 and Twist2. These include dimer choice, phosphoregulation, protein–protein interactions and spatial-temporal expression. Dimer choice is mainly influenced by the availability of other bHLH proteins within the cell and the phosphorylation state of these proteins (26–28). It is known that Class B bHLH factors can form functional homodimers as well as heterodimers with Class A bHLH factors including E12/E47. However, heterodimer formation among class B bHLH proteins has also been reported as in the case with Twist1 and Hand2 dimer formation (Figure 2D) (6,29). Id proteins have great affinity for E12 and compete against class B bHLH proteins for E12 binding (26,28,30). Therefore, Id proteins actively alter dimerization pools by binding and sequestering bHLH factors, without themselves being able to bind DNA. The composition of these partner pools will ultimately determine the expression profile and therefore the cellular response. Hence, the relative stoichiometry of these factors influence whether Twist1 or Twist2 form heterodimers with E12, or homodimer formation is favored due to Id-mediated E12 sequestration.Figure 2.

Bottom Line: Regulatory outcomes of Twist1 and Twist2 are themselves controlled by spatial-temporal expression, phosphoregulation, dimer choice and cellular localization.Although these two proteins are highly conserved and exhibit similar functions in vitro, emerging literature have demonstrated different roles in vivo.The involvement of Twist1 and Twist2 in a broad spectrum of regulatory pathways highlights the importance of understanding their roles in normal development, homeostasis and disease.

View Article: PubMed Central - PubMed

Affiliation: Human Molecular Genetics Lab, Department of Biochemistry, School of Medicine University of Puerto Rico, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936, USA.

ABSTRACT
Twist1 and Twist2 are highly conserved members of the Twist subfamily of bHLH proteins responsible for the transcriptional regulation of the developmental programs in mesenchymal cell lineages. The regulation of such processes requires that Twist1 and Twist2 function as molecular switches to activate and repress target genes by employing several direct and indirect mechanisms. Modes of action by these proteins include direct DNA binding to conserved E-box sequences and recruitment of coactivators or repressors, sequestration of E-protein modulators, and interruption of proper activator/repressor function through protein-protein interactions. Regulatory outcomes of Twist1 and Twist2 are themselves controlled by spatial-temporal expression, phosphoregulation, dimer choice and cellular localization. Although these two proteins are highly conserved and exhibit similar functions in vitro, emerging literature have demonstrated different roles in vivo. The involvement of Twist1 and Twist2 in a broad spectrum of regulatory pathways highlights the importance of understanding their roles in normal development, homeostasis and disease. Here we focus on the mechanistic models of transcriptional regulation and summarize the similarities and differences between Twist1 and Twist2 in the context of myogenesis, osteogenesis, immune system development and cancer.

Show MeSH
Related in: MedlinePlus